Substituted imidazole 4-carboxamides as cholecystokinin-1 receptor modulators

ABSTRACT

Certain novel substituted imidazole 4-carboxamides are ligands of the human cholecystokinin receptor and, in particular, are selective ligands of the human cholecystokinin-1 receptor (CCK-1R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the modulation of CCK-1R , such as obesity, and diabetes.

BACKGROUND OF THE INVENTION

Obesity is a major health concern in Western societies. It is estimatedthat about 97 million adults in the United States are overweight orobese. Obesity is now recognized as a chronic disease that requirestreatment to reduce its associated health risks. The medical problemsassociated with obesity, which can be serious and life-threatening,include hypertension; type 2 diabetes mellitus; elevated plasma insulinconcentrations; insulin resistance; hyperinsulinemia; glucoseintolerance; dyslipidemias; hyperlipidemia; endometrial, breast,prostate and colon cancer; osteoarthritis; respiratory complications,such as obstructive sleep apnea; cholescystitis; cholelithiasis; gout;gallstones; gall bladder disease; respiratory problems; psychologicaldisorders (such as depression, eating disorders, distorted body imageand low self esteem); arteriosclerosis; heart disease; abnormal heartrhythms; angina pectoris; and heart arrythmias (Kopelman, P. G., Nature404, 635-643 (2000)). Obesity is further associated with premature deathand with a significant increase in mortality and morbidity from stroke,myocardial infarction, congestive heart failure, coronary heart disease,and sudden death. Recent studies have found that obesity and itsassociated health risks also affect children and adolescents. Accordingto the Centers for Disease Control, 15 percent of children andadolescents are defined as overweight and obese, a doubling since theearly 1970s. Important outcomes for the treatment of obesity includeweight loss, and weight management to improve cardiovascular andmetabolic health and to reduce obesity-related morbidity and mortality.It has been shown that 5-10% loss of body weight can substantiallyimprove metabolic values, such as blood glucose, blood pressure, andlipid concentrations, and may reduce morbidity and mortality.

Cholecystokinin (CCK) is a brain-gut peptide that acts as agastrointestinal hormone, neurotransmitter and neuromodulator in thecentral and the peripheral nervous systems. It has been shown that CCKis released from mucosal 1-cells of the duodenum and jejunum in responseto a meal, particularly in response to fat or protein in the meal. Oncereleased, CCK initiates a number of responses coordinated to promotedigestion and regulate food intake, including mediating bile emptyingfrom the gall bladder, regulating the release of digestive enzymes fromthe pancreas, controlling gastric emptying by regulation of the pyloricsphincter, as well as neuronal signaling to the central nervous systemvia vagal afferent neurons. Neuronal CCK is believed to mediate a numberof events within the CNS, including modulating dopaminergicneurotransmission and anxiogenic effects, as well as affecting cognitionand nociception. See, e.g., J. N. Crawley and R. L. Corwin, 1994,Peptides, 15:731-755; N. S. Baber, C. T. Dourish, and D. R. Hill, Pain(1989), 39(3), 307-28; and P. De Tullio, J. Delarge and B. Pirotte,Expert Opinion on Investigational Drugs (2000), 9(1), 129-146.Cholecystokinin has been shown to mediate its diverse hormonal andneuromodulatory functions through two receptor subtypes: the CCK-A(CCK-1) and CCK-B (CCK-2) subtypes (see, e.g., G. N. Woodruff and J.Hughes, Annu. Rev. Pharmacol. Toxicol. (1991), 31: 469-501). Both CCK-1and CCK-2 receptor subtypes belong to the seven transmembraneG-protein-coupled superfamily of receptors. A number of studies suggestthat CCK mediates its satiety effect through the CCK-1 receptor, whichrelays the postprandial satiety signal via the vagal afferents to theCNS. See, e.g., G. P. Smith et al., Science 213 (1981) pp. 1036-1037;and J. N. Crawley et al., J. Pharmacol. Exp. Ther., 257 (1991) pp.1076-1080. The nucleotide sequences of the peripheral CCK-1 receptor andcentral CCK-1 receptor are identical in humans. See, e.g., S. A. Wank etal., (1994), NY Acad. Sci. 713, pp. 49-66.

It has been reported that cholecystokinin (CCK) inhibits gastricemptying and increases satiety in a variety of species, includinghumans, resulting in a reduction of food intake (Moran, T. H. Physiology& Behavior 2004, 82, 175-180). Selective CCK1R antagonists have beenshown to reverse the anorexigenic effect of CCK thus increasing foodintake and meal size in several species, including humans (Beglinger, C.et. al. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2001, 280,R1149-R1154). Conversely, administration of CCK1R agonists to a varietyof species, including humans, results in a reduction of food intake(Geary, N. Physiology & Behavior 2004, 81, 719-733). Consequently,selective small molecule CCK1R agonists are useful for the treatment orprevention of obesity and related metabolic disorders such as diabetesand dyslipidemia (Woods, S. C. Am. J. Gastrointest. Liver Physiol. 2004,286, G7-13; Moran, T. H., Kinzig, K. P. Am. J. Gastrointest. LiverPhysiol. 2004, 286, G183-G188). In humans, bulimia nervosa has beenlinked with reduced secretion of postprandial CCK (Deylin, M. J. et. al.J. Pharmacol. Exp. Ther. 1987, 241, 100-116), lower CCK concentrationsin cerebrospinal fluid (Lydiard, R. B. et. al. Am. J. Psychiatry 1993,150, 1099-1101), and lower CCK levels in T lymphocytes which couldreflect central CCK secretion levels (Brambilla, F. et. al. PsychiatryResearch 1995, 37, 51-56). Accordingly, CCK1R agonists are also usefulin treating, preventing, or diagnosing bulimia nervosa and relatedeating disorders.

CCK agonists stimulate gallbladder contraction, stimulate pancreaticenzyme secretions, stimulate intestinal blood flow, and affectintestinal motor activity (See Rehfeld, J. F. Best Practice & Res. Clin.Endocrin. & Metab. 2004, 18, 569-586). Consequently, CCK1R agonists areuseful for the treatment, prevention, or diagnosis of disorders relatedto the gall bladder including, but not limited to, cholecystitis(inflammation of the gallbladder) and cholelithiasis (gallstones).Furthermore, CCK agonists are useful for the treatment, prevention, ordiagnosis of disorders related to the pancreas. Finally, CCK1R agonistsare useful for the treatment, prevention, or diagnosis of disordersrelated to the gastrointestinal tract and gastrointestinal motility. CCKreceptors are abundant in the central nervous system, and agonists canbe used for the treatment, prevention, or diagnosis of emotional orsexual behavior disorders and memory disorders (Itoh, S.; et. al. DrugDevelop. Res. 1990, 21, 257-276). Furthermore, CCK agonists can be usedfor the treatment, prevention, or diagnosis of tardive dyskinesia(Nishikawa, T. et. al. Prog. Neuropsycho-pharmacol. Biol. Psych. 1988,12, 903-812; Bignon, E. et. al. J. Pharm. Exp. Ther. 1999, 289,752-761), Parkinson's disease (Bednar, I. et. al. Biogenic Amine, 1996,12, 275-284), schizophrenia, and psychosis (Crawley, J. N. Trends inPharmacol. Sci., 1991, 12, 232-236).

Imidazole compounds useful for the treatment of obesity and obesityrelated disorders have been disclosed in WO 01/085723, WO 03/040107, WO03/063781, WO 03/007887, WO 2004/094407, WO 2005/009974, WO 2005/040130,WO 2005/063716, WO 2005/095354, US 2005/0054679, US 2005/0124660, US2005/0197377, U.S. Pat. No. 6,960,601, and J. Med. Chem. 2005, 48,1823-1838. Other imidazoles are disclosed in J. Med. Chem. 2005, 48,2638-2645; J. Med. Chem., 2002, 45, 4655-4668; J. Med. Chem. 2000, 43,3168-3185; and J. Med. Chem. 1997, 40, 1634-1647.

Because of the unresolved deficiencies of the various pharmacologicalagents discussed above, there is a continuing need for a weight losstreatment with enhanced efficacy and fewer undesirable side effects. Theinstant invention addresses this problem by providing CCK receptoragonists, and in particular selective agonists of the cholecystokinin-1receptor (CCK-1R), useful in the treatment and prevention of obesity andobesity-related disorders, including diabetes.

It is therefore an object of the present invention to providesubstituted imidazole 4-carboxamides which are selective agonists of thecholecystokinin-1 (CCK-1R) receptor. It is another object of the presentinvention to provide substituted imidazole 4-carboxamides which arecholecystokinin-1 receptor agonists and thereby useful to treat obesity,diabetes, and obesity related disorders. It is another object of thepresent invention to provide pharmaceutical compositions comprising thecholecystokinin-1 receptor agonists of the present invention with apharmaceutically acceptable carrier. It is another object of the presentinvention to provide methods for the treatment or prevention ofdisorders, diseases, or conditions responsive to the activation of thecholecystokinin-1 receptor in a mammal in need thereof by administeringthe compounds and pharmaceutical compositions of the present invention.It is another object of the present invention to provide methods for thetreatment or prevention of obesity, diabetes mellitus, and obesityrelated disorders by administering the compounds and pharmaceuticalcompositions of the present invention to a mammal in need thereof. Theseand other objects will become readily apparent from the detaileddescription that follows.

SUMMARY OF THE INVENTION

The present invention relates to novel substituted imidazole4-carboxamides of formula I:

The compounds of formula I are effective as cholecystokinin receptorligands and are particularly effective as selective ligands of thecholecystokinin-1 receptor. They are therefore useful for the treatmentand/or prevention of disorders responsive to the modulation of thecholecystokinin-1 receptor, such as obesity, diabetes, andobesity-related disorders.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

The present invention also relates to methods for the treatment orprevention of disorders, diseases, or conditions responsive to themodulation of the cholecystokinin-1 receptor in a mammal in need thereofby administering the compounds and pharmaceutical compositions of thepresent invention.

The present invention further relates to the use of the compounds of thepresent invention in the preparation of a medicament useful for thetreatment or prevention of disorders, diseases, or conditions responsiveto the modulation of the cholecystokinin-1 receptor in a mammal in needthereof by administering the compounds and pharmaceutical compositionsof the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to substituted imidazole 4-carboxamidesuseful as cholecystokinin receptor modulators, in particular, asselective cholecystokinin-1 receptor agonists. Compounds of the presentinvention are described by formula I:

or a pharmaceutically acceptable salt thereof; wherein

X is N or CR¹⁶;

R¹, R², R³ and R⁴ are each independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) —OH,    -   (4) —C₁₋₆alkyl,    -   (5) —C₁₋₆alkoxy,    -   (6) —(CH₂)_(n)NR¹¹NR¹²,    -   (7) —(CH₂)_(n)NR¹³R¹⁵, and    -   (8) —(CH₂)_(n)SR¹³,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five substituents selected from halogen, OH, C₁₋₆alkyl,        and C₁₋₆alkoxy, or R² and R³ or R³ and R⁴ together with the        atoms to which they are attached form a 4-8 membered ring        containing 0-2 heteroatoms independently selected from oxygen,        sulfur, and N—R¹⁵, and wherein the 4-8 membered ring is        unsubstituted or substituted with a substituent selected from        —OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy;        R⁵, R⁶ and R⁷ are each independently selected from the group        consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) —OH,    -   (4) —C₁₋₆alkyl, and    -   (5) —C₁₋₆alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five substituents selected from halogen, OH, C₁₋₆alkyl,        and C₁₋₆alkoxy, or R⁵ and R⁶ together with the atoms to which        they are attached form a 4-8 membered ring containing 0-2        heteroatoms independently selected from oxygen, sulfur, and        N—R¹⁵, and wherein the 4-8 membered ring is unsubstituted or        substituted with a substituent selected from —OH, halogen,        C₁₋₆alkyl, and C₁₋₆alkoxy;        R⁸ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) —C₁₋₆alkyl,    -   (4) —C₁₋₆alkoxy, and    -   (5) —C₃₋₆cycloalkyl;        wherein alkyl, alkoxy and cycloalkyl are unsubstituted or        substituted with one to five substituents selected from halogen        and —OH;        each R⁹ is independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) —CF₃,    -   (3) —OH,    -   (4) —CN,    -   (5) —C₁₋₆alkyl,    -   (6) —C₁₋₆alkoxy,    -   (7) —(CH₂)_(n)NR¹⁷R¹⁸,    -   (8) -a 5-10 membered aromatic monocyclic or bicyclic        heterocyclic ring, and    -   (9) phenyl,        wherein alkyl, alkoxy, the heterocyclic ring and phenyl are        unsubstituted or substituted with one or more substituents        selected from C₁₋₆alkyl, —OH, phenyl, C₁₋₆alkoxy, —CF₃, —CN, and        halogen;        each R¹⁰ is independently selected from the group consisting of:    -   (1) —(CH₂)_(n)halogen,    -   (2) —(CH₂)_(n)CN,    -   (3) —(CH₂)_(n)NO₂,    -   (4) —(CH₂)_(n)OR¹²,    -   (5) —C₂₋₆alkene-CO₂R¹²,    -   (6) —(CH₂)_(n)COR¹³,    -   (7) —(CH₂)_(n)CO₂R¹²,    -   (8) —(CH₂)_(n)C(O)NR¹¹R¹²,    -   (9) —(CH₂)_(n)CONR¹¹COR¹³,    -   (10) —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹²,    -   (11) —(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹²)₂,    -   (12) —(CH₂)_(n)NR¹¹R¹²,    -   (13) —(CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,    -   (14) —(CH₂)_(n)NR¹¹C(O)R¹³,    -   (15) —(CH₂)_(n)OC(O)NR¹¹R¹²,    -   (16) —(CH₂)_(n)NR¹¹CO₂R¹²,    -   (17) —(CH₂)_(n)NR¹¹SO₂R¹³,    -   (18) —(CH₂)_(n)SO₂NR¹¹R¹²,    -   (19) —(CH₂)_(n)SO₂R¹³,    -   (20) —(CH₂)_(n)SO₃H,    -   (21) —(CH₂)_(n)PO₂R¹³,    -   (22) —(CH₂)_(n)PO₃H,    -   (23) —C₁₋₆alkyl,    -   (24) —(CH₂)_(n)aryl,    -   (25) —(CH₂)_(n)heteroaryl,    -   (26) —(CH₂)_(n)heterocycloalkyl, and    -   (27) —(CH₂)_(n)C₃₋₈cycloalkyl,        wherein alkyl is substituted with one to five substituents        selected from —C₁₋₆alkyl, oxo, halogen, —C₁₋₆alkoxy,        —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,        —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents independently        selected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl,        wherein alkene and —(CH₂)_(n) are unsubstituted or substituted        with one to five substituents selected from —C₁₋₆alkyl, oxo,        halogen, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃,        —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents independently        selected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and        wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are        unsubstituted or substituted with one to five substituents        independently selected from oxo, halogen, —C₁₋₆alkoxy,        —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,        —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents independently        selected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl;        each R¹¹ and R¹² is independently hydrogen or R¹³, or R¹¹ and        R¹² together with the nitrogen to which they are attached form a        4-8 membered heterocyclic ring containing 0-2 additional        heteroatoms selected from oxygen, sulfur, and NR¹⁵, and wherein        the 4-8 membered heterocyclic ring is unsubstituted or        substituted with one to five substituents independently selected        from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH,        —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,        —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene and alkyl        and alkoxy are unsubstituted or substituted with one to five        substituents selected from halogen, —OH, —SO₃H, —CO₂H, and        —CO₂C₁₋₆alkyl;        each R¹³ is independently selected from the group consisting of:    -   (1) —C₁₋₈alkyl,    -   (2) —(CH₂)_(n)OH,    -   (3) —(CH₂)_(n)C₃₋₈cycloalkyl,    -   (4) —(CH₂)_(n)C₂₋₈ heterocycloalkyl,    -   (5) —(CH₂)_(n)aryl, and    -   (6) —(CH₂)_(n)heteroaryl,        wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂)_(n) are        unsubstituted or substituted with one to eight substituents        selected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,        —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,        —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents selected from        halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein aryl        and heteroaryl are unsubstituted or substituted with one to        eight substituents independently selected from halogen,        —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,        —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, (CH₂)_(n)CO₂H,        —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl        and alkoxy are unsubstituted or substituted with one to five        substituents selected from halogen, —OH, —SO₃H, —CO₂H, and        —CO₂C₁₋₆alkyl;        each R¹⁴ is independently selected from the group consisting of:    -   (1) —C₁₋₆alkyl,    -   (2) —(CH₂)_(n)C₃₋₈cycloalkyl,    -   (3) —(CH₂)_(n)C₂₋₈ heterocycloalkyl,    -   (4) —(CH₂)_(n)aryl, and    -   (5) —(CH₂)_(n)heteroaryl,        wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl are unsubstituted or substituted with one to five        substituents independently selected from —OH, oxo, halogen, —CN,        —(CH₂)_(n)CO₂H, —SO₃H, C₁₋₆alkyl, and C₁₋₆alkoxy, and alkyl and        alkoxy are unsubstituted or substituted with one to five        substituents selected from halogen, —CO₂H, and —SO₃H;        each R¹⁵ is independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₃₋₈cycloalkyl,    -   (4) —SO₂R¹⁴,    -   (5) —COR¹⁴,    -   (6) —CO₂R⁴, and    -   (7) —CO₂H,        wherein alkyl and cycloalkyl are unsubstituted or substituted        with one to five substituents selected from halogen, —OH, and        —(CH₂)_(n)CO₂H;        R¹⁶ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —CF₃,    -   (3) —OH,    -   (4) —CN,    -   (5) —C₁₋₆alkyl,    -   (6) —C₁₋₆alkoxy,    -   (7) —(CH₂)_(n)C₃₋₈cycloalkyl,    -   (8) —(CH₂)_(n)NR¹⁷R¹⁸,    -   (9) -a 5-10 membered aromatic monocyclic or bicyclic        heterocyclic ring, and    -   (10) phenyl,        wherein alkyl, alkoxy, cycloalkyl, the heterocyclic ring and        phenyl are unsubstituted or substituted with one or more        substituents selected from C₁₋₆alkyl, —OH, phenyl, C₁₋₆alkoxy,        —CF₃, —CN, and halogen;        each R¹⁷ and R¹⁵ is independently selected from the group        consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —(CH₂)_(n)C₃₋₈cycloalkyl, and    -   (4) —(CH₂)_(n)heterocycloalkyl,        or R¹⁷ and R¹⁸ together with the nitrogen to which they are        attached form a 4-8 membered heterocyclic ring containing 0-2        additional heteroatoms selected from oxygen, sulfur, and NR¹⁵,        and wherein alkyl, cycloalkyl, heterocycloalkyl and the 4-8        membered heterocyclic ring are unsubstituted or substituted with        one to five substituents independently selected from —OH, oxo,        halogen, —CN, CF₃, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,        —(CH₂)_(n)SO₃H, —C₁₋₆alkyl, and C₁₋₆alkoxy, and alkyl and alkoxy        are unsubstituted or substituted with one to five substituents        selected from halogen, —CO₂H, and —SO₃H;        each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;        each m is independently 1, 2, 3 or 4; and        each p is independently 0, 1, 2, 3 or 4.

In a further embodiment of the compounds of the present invention, thereare provided compounds of formula II:

or a pharmaceutically acceptable salt thereof; whereinR², R³ and R⁴ are each independently selected from the group consistingof:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) —OH,    -   (4) —C₁₋₆alkyl,    -   (5) —C₁₋₆alkoxy,    -   (6) —(CH₂)_(n)NR¹¹R¹²,    -   (7) —(CH₂)_(n)NR¹³R¹⁵, and    -   (8) —(CH₂)_(n)SR¹³,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five substituents selected from halogen, OH, C₁₋₆alkyl,        and C₁₋₆alkoxy, or R² and R³ or R³ and R⁴ together with the        atoms to which they are attached form a 4-8 membered ring        containing 0-2 heteroatoms independently selected from oxygen,        sulfur, and N—R¹⁵, and wherein the 4-8 membered ring is        unsubstituted or substituted with a substituent selected from        —OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy;        R⁵, R⁶ and R⁷ are each independently selected from the group        consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) —C₁₋₆alkyl, and    -   (4) —C₁₋₆alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five substituents selected from halogen, OH, C₁₋₆alkyl,        and C₁₋₆alkoxy;        R⁸ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) —C₁₋₆alkyl,    -   (4) —C₁₋₆alkoxy, and    -   (5) —C₃₋₆cycloalkyl;        each R⁹ is independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) —CF₃,    -   (3) —OH,    -   (4) —CN,    -   (5) —C₁₋₆alkyl, unsubstituted or substituted with —OH or phenyl,    -   (6) —C₁₋₆alkoxy,    -   (7) —(CH₂)_(n)NR¹⁷R¹⁸,    -   (8) -a 5-10 membered aromatic monocyclic or bicyclic        heterocyclic ring, and    -   (9) phenyl, unsubstituted or substituted with one or more        substituents selected from C₁₋₆alkyl, —OH, C₁₋₆alkoxy, —CF₃,        —CN, and halogen;        each R¹⁰ is independently selected from the group consisting of:    -   (1) —(CH₂)_(n)halogen,    -   (2) —(CH₂)_(n)CN,    -   (3) —(CH₂)_(n)NO₂,    -   (4) —(CH₂)_(n)OR¹²,    -   (5) —C₂₋₆alkene-CO₂R¹²,    -   (6) —(CH₂)_(n)COR¹³,    -   (7) —(CH₂)_(n)CO₂R¹²,    -   (8) —(CH₂)_(n)C(O)NR¹¹R¹²,    -   (9) —(CH₂)_(n)CONR¹¹COR¹³,    -   (10) —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹²,    -   (11) —(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹²)₂,    -   (12) —(CH₂)_(n)NR¹¹R¹²,    -   (13) —(CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,    -   (14) —(CH₂)_(n)NR¹¹C(O)R¹³,    -   (15) —(CH₂)_(n)OC(O)NR¹¹R¹²,    -   (16) —(CH₂)_(n)NR^(l1)CO₂R¹²,    -   (17) —(CH₂)_(n)NR¹¹SO₂R¹³,    -   (18) —(CH₂)_(n)SO₂NR¹¹R¹²,    -   (19) —(CH₂)_(n)SO₂R¹³,    -   (20) —(CH₂)_(n)SO₃H,    -   (21) —(CH₂)_(n)PO₂R¹³,    -   (22) —(CH₂)_(n)PO₃H,    -   (23) —C₁₋₆alkyl,    -   (24) —(CH₂)_(n)aryl,    -   (25) —(CH₂)_(n)heteroaryl,    -   (26) —(CH₂)_(n)heterocycloalkyl, and    -   (27) —(CH₂)_(n)C₃₋₈cycloalkyl,        wherein alkyl is substituted with one to five substituents        selected from —C₁₋₆alkyl, oxo, halogen, —C₁₋₆alkoxy,        —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,        —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents independently        selected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl,        wherein alkene and —(CH₂)_(n) are unsubstituted or substituted        with one to five substituents selected from —C₁₋₆alkyl, oxo,        halogen, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃,        —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents independently        selected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and        wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are        unsubstituted or substituted with one to five substituents        independently selected from oxo, halogen, —C₁₋₆alkoxy,        —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,        —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents independently        selected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl;        each R¹¹ and R¹² is independently hydrogen or R¹³, or R¹¹ and        R¹² together with the nitrogen to which they are attached form a        4-8 membered heterocyclic ring containing 0-2 additional        heteroatoms selected from oxygen, sulfur, and NR¹⁵, and wherein        the 4-8 membered heterocyclic ring is unsubstituted or        substituted with one to five substituents independently selected        from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH,        —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,        —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene and alkyl        and alkoxy are unsubstituted or substituted with one to five        substituents selected from halogen, —OH, —SO₃H, —CO₂H, and        —CO₂C₁₋₆alkyl;        each R¹³ is independently selected from the group consisting of:    -   (1) —C₁₋₈alkyl,    -   (2) —(CH₂)_(n)OH,    -   (3) —(CH₂)_(n)C₃₋₈cycloalkyl,    -   (4) —(CH₂)_(n)C₂₋₈ heterocycloalkyl,    -   (5) —(CH₂)_(n)aryl, and    -   (6) —(CH₂)_(n)heteroaryl,        wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂)_(n) are        unsubstituted or substituted with one to eight substituents        selected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,        —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,        —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents selected from        halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein aryl        and heteroaryl are unsubstituted or substituted with one to        eight substituents independently selected from halogen,        —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,        —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,        —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl        and alkoxy are unsubstituted or substituted with one to five        substituents selected from halogen, —OH, —SO₃H, —CO₂H, and        —CO₂C₁₋₆alkyl;        each R¹⁴ is independently selected from the group consisting of:    -   (1) —C₁₋₆alkyl, unsubstituted or substituted with one to five        substituents selected from halogen, hydrogen, —OH, —CO₂H, and        —SO₃H,    -   (2) —(CH₂)_(n)C₃₋₈cycloalkyl, unsubstituted or substituted with        one to five substituents selected from halogen, hydrogen, —OH,        —CO₂H, and —SO₃H,    -   (3) —(CH₂)_(n)C₂₋₈ heterocycloalkyl, unsubstituted or        substituted with one to five substituents selected from halogen,        —OH, oxo, —C₁₋₆alkyl, C₁₋₆alkoxy, and —(CH₂)_(n)CO₂H, and alkyl        and alkoxy are unsubstituted or substituted with one to five        halogens,    -   (4) —(CH₂)_(n)aryl, unsubstituted or substituted with one to        five substituents selected from —OH, halogen, —CN, —CO₂H, —SO₃H,        C₁-C₆alkyl, and C₁₋₆alkoxy, and alkyl and alkoxy are        unsubstituted or substituted with one to five substituents        selected from halogen, —OH, —CO₂H, and —SO₃H, and    -   (5) —(CH₂)_(n)heteroaryl, unsubstituted or substituted with one        to five substituents independently selected from —OH, halogen,        —CN, —CO₂H, —SO₃H, C₁₋₆alkyl, and C₁₋₆alkoxy, and alkyl and        alkoxy are unsubstituted or substituted with one to five        substituents selected from halogen, —CO₂H, and —SO₃H;        each R¹⁵ is independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₃₋₈cycloalkyl,    -   (4) —SO₂R¹⁴,    -   (5) —COR¹⁴,    -   (6) —CO₂R¹⁴, and    -   (7) —CO₂H,        wherein alkyl and cycloalkyl are unsubstituted or substituted        with one to five substituents selected from halogen, —OH, and        —(CH₂)_(n)CO₂H;        each R¹⁷ and R¹⁸ is independently selected from the group        consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —(CH₂)_(n)C₃₋₈cycloalkyl, and    -   (4) —(CH₂)_(n)heterocycloalkyl,        or R⁷ and R¹⁸ together with the nitrogen to which they are        attached form a 4-8 membered heterocyclic ring containing 0-2        additional heteroatoms selected from oxygen, sulfur, and NR¹⁵,        and wherein alkyl, cycloalkyl, heterocycloalkyl and the 4-8        membered heterocyclic ring are unsubstituted or substituted with        one to five substituents independently selected from —OH, oxo,        halogen, —CN, CF₃, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,        —(CH₂)_(n)SO₃H, —C₁₋₆alkyl, and C₁₋₆alkoxy, and alkyl and alkoxy        are unsubstituted or substituted with one to five substituents        selected from halogen, —CO₂H, and —SO₃H;        each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; and        each m is independently 1, 2, 3 or 4.

In a further embodiment of the compounds of the present invention, thereare provided compounds of formula III:

or a pharmaceutically acceptable salt thereof; whereinR², R³ and R⁴ are each independently selected from the group consistingof:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) —OH,    -   (4) —C₁₋₆alkyl,    -   (5) —C₁₋₆alkoxy,    -   (6) —(CH₂)_(n)NR¹¹R¹²,    -   (7) —(CH₂)_(n)NR¹³R¹⁵, and    -   (8) —(CH₂)_(n)SR¹³,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five substituents selected from halogen, OH, C₁₋₆alkyl,        and C₁₋₆alkoxy, or R² and R³ or R³ and R⁴ together with the        atoms to which they are attached form a 4-8 membered ring        containing 0-2 heteroatoms independently selected from oxygen,        sulfur, and N—R¹⁵, and wherein the 4-8 membered ring is        unsubstituted or substituted with a substituent selected from        —OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy;        R⁵, R⁶ and R⁷ are each independently selected from the group        consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) —C₁₋₆alkyl, and    -   (4) —C₁₋₆alkoxy,        wherein alkyl and alkoxy are unsubstituted or substituted with        one to five substituents selected from halogen, OH, C₁₋₆alkyl,        and C₁₋₆alkoxy;        R⁸ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) —C₁₋₆alkyl,    -   (4) —C₁₋₆alkoxy, and    -   (5) —C₃₋₆cycloalkyl;        each R⁹ is independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) —CF₃,    -   (3) —OH,    -   (4) —CN,    -   (5) —C₁₋₆alkyl, unsubstituted or substituted with —OH or phenyl,    -   (6) —C₁₋₆alkoxy,    -   (7) —(CH₂)_(n)NR¹⁷R¹³,    -   (8) -a 5-10 membered aromatic monocyclic or bicyclic        heterocyclic ring, and    -   (9) phenyl, unsubstituted or substituted with one or more        substituents selected from C₁₋₆alkyl, —OH, C₁₋₆alkoxy, —CF₃,        —CN, and halogen;        each R¹⁰ is independently selected from the group consisting of:    -   (1) —(CH₂)_(n)halogen,    -   (2) —(CH₂)_(n)CN,    -   (3) —(CH₂)_(n)NO₂,    -   (4) —(CH₂)_(n)OR¹²,    -   (5) —C₂₋₆alkene-CO₂R¹²,    -   (6) —(CH₂)_(n)COR¹³,    -   (7) —(CH₂)_(n)CO₂R¹²,    -   (8) —(CH₂)_(n)C(O)NR¹¹R¹²,    -   (9) —(CH₂)_(n)CONR¹¹COR¹³,    -   (10) —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹²,    -   (11) —(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹²)₂,    -   (12) —(CH₂)_(n)NR¹¹R¹²,    -   (13) —(CH₂)_(n)NR¹¹C(O)NR¹¹R¹²,    -   (14) —(CH₂)_(n)NR¹¹C(O)R¹³,    -   (15) —(CH₂)_(n)OC(O)NR¹¹R¹²,    -   (16) —(CH₂)_(n)NR¹¹CO₂R¹²,    -   (17) —(CH₂)_(n)NR¹¹SO₂R¹³,    -   (18) —(CH₂)_(n)SO₂NR¹¹R¹²,    -   (19) —(CH₂)_(n)SO₂R¹³,    -   (20) —(CH₂)_(n)SO₃H,    -   (21) —(CH₂)_(n)PO₂R¹³,    -   (22) —(CH₂)_(n)PO₃H,    -   (23) —C₁₋₆alkyl,    -   (24) —(CH₂)_(n)aryl,    -   (25) —(CH₂)_(n)heteroaryl,    -   (26) —(CH₂)_(n)heterocycloalkyl, and    -   (27) —(CH₂)_(n)C₃₋₈cycloalkyl,        wherein alkyl is substituted with one to five substituents        selected from —C₁₋₆alkyl, oxo, halogen, —C₁₋₆alkoxy,        —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,        —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents independently        selected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl,        wherein alkene and —(CH₂), are unsubstituted or substituted with        one to five substituents selected from —C₁₋₆alkyl, oxo, halogen,        —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃,        —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents independently        selected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and        wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are        unsubstituted or substituted with one to five substituents        independently selected from oxo, halogen, —C₁₋₆alkoxy,        —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,        —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents independently        selected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl;        each R¹¹ and R¹² is independently hydrogen or R¹³, or R¹¹ and        R¹² together with the nitrogen to which they are attached form a        4-8 membered heterocyclic ring containing 0-2 additional        heteroatoms selected from oxygen, sulfur, and NR¹⁵, and wherein        the 4-8 membered heterocyclic ring is unsubstituted or        substituted with one to five substituents independently selected        from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH,        —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,        —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene and alkyl        and alkoxy are unsubstituted or substituted with one to five        substituents selected from halogen, —OH, —SO₃H, —CO₂H, and        —CO₂C₁₋₆alkyl;        each R¹³ is independently selected from the group consisting of:    -   (1) —C₁₋₈alkyl,    -   (2) —(CH₂)_(n)OH,    -   (3) —(CH₂)_(n)C₃₋₈cycloalkyl,    -   (4) —(CH₂)_(n)C₂₋₈ heterocycloalkyl,    -   (5) —(CH₂)_(n)aryl, and    -   (6) —(CH₂)_(n)heteroaryl,        wherein alkyl, cycloalkyl, heterocycloalkyl, and —(CH₂)_(n) are        unsubstituted or substituted with one to eight substituents        selected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,        —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,        —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and        —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted        or substituted with one to five substituents selected from        halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein aryl        and heteroaryl are unsubstituted or substituted with one to        eight substituents independently selected from halogen,        —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,        —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,        —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl        and alkoxy are unsubstituted or substituted with one to five        substituents selected from halogen, —OH, —SO₃H, —CO₂H, and        —CO₂C₁₋₆alkyl;        each R¹⁴ is independently selected from the group consisting of:    -   (1) —C₁₋₆alkyl, unsubstituted or substituted with one to five        substituents selected from halogen, hydrogen, —OH, —CO₂H, and        —SO₃H,    -   (2) —(CH₂)_(n)C₃₋₈cycloalkyl, unsubstituted or substituted with        one to five substituents selected from halogen, hydrogen, —OH,        —CO₂H, and —SO₃H,    -   (3) —(CH₂)_(n)C₂₋₈ heterocycloalkyl, unsubstituted or        substituted with one to five substituents selected from halogen,        —OH, oxo, —C₁₋₆alkyl, C₁₋₆alkoxy, and —(CH₂)_(n)CO₂H, and alkyl        and alkoxy are unsubstituted or substituted with one to five        halogens,    -   (4) —(CH₂)_(n)aryl, unsubstituted or substituted with one to        five substituents selected from —OH, halogen, —CN, —CO₂H, —SO₃H,        C₁-C₆alkyl, and C₁₋₆alkoxy, and alkyl and alkoxy are        unsubstituted or substituted with one to five substituents        selected from halogen, —OH, —CO₂H, and —SO₃H, and    -   (5) —(CH₂)_(n)heteroaryl, unsubstituted or substituted with one        to five substituents independently selected from —OH, halogen,        —CN, —CO₂H, —SO₃H, C₁₋₆alkyl, and C₁₋₆alkoxy, and alkyl and        alkoxy are unsubstituted or substituted with one to five        substituents selected from halogen, —CO₂H, and —SO₃H;        each R¹⁵ is independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₃₋₈cycloalkyl,    -   (4) —SO₂R¹⁴,    -   (5) —COR¹⁴,    -   (6) —CO₂R⁴, and    -   (7) —CO₂H,        wherein alkyl and cycloalkyl are unsubstituted or substituted        with one to five substituents selected from halogen, —OH, and        —(CH₂)_(n)CO₂H;        R¹⁶ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —CF₃,    -   (3) —OH,    -   (4) —CN,    -   (5) —C₁₋₆alkyl, unsubstituted or substituted with —OH or phenyl,    -   (6) —C₁₋₆alkoxy,    -   (7) —(CH₂)_(n)C₃₋₈cycloalkyl,    -   (8) —(CH₂)_(n)NR¹⁷R¹⁸,    -   (9) -a 5-10 membered aromatic monocyclic or bicyclic        heterocyclic ring, and    -   (10) phenyl, unsubstituted or substituted with one or more        substituents selected from C₁₋₆alkyl, —OH, C₁₋₆alkoxy, —CF₃,        —CN, and halogen;        each R¹⁷ and R¹⁸ is independently selected from the group        consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —(CH₂)_(n)C₃₋₈cycloalkyl, and    -   (4) —(CH₂)_(n) heterocycloalkyl,        or R¹⁷ and R¹⁸ together with the nitrogen to which they are        attached form a 4-8 membered heterocyclic ring containing 0-2        additional heteroatoms selected from oxygen, sulfur, and NR¹⁵,        and wherein alkyl, cycloalkyl, heterocycloalkyl and the 4-8        membered heterocyclic ring are unsubstituted or substituted with        one to five substituents independently selected from —OH, oxo,        halogen, —CN, CF₃, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,        —(CH₂)_(n)SO₃H, —C₁₋₆alkyl, and C₁₋₆alkoxy, and alkyl and alkoxy        are unsubstituted or substituted with one to five substituents        selected from halogen, —CO₂H, and —SO₃H;        each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; and        each m is independently 1, 2, 3 or 4.

In one class of the embodiments, X is N or CR¹⁶. In a subclass of thisclass, X is N. In another subclass of this class, X is CR¹⁶. In asubclass of this subclass, X is CH. In another subclass of this subclassX is COH.

In another class of the embodiments, R¹, R², R³ and R⁴ are each selectedfrom the group consisting of: hydrogen, halogen, —OH, —C₁₋₆alkyl, and—C₁₋₆alkoxy, wherein alkyl and alkoxy are unsubstituted or substitutedwith one to five substituents selected from halogen, OH, C₁₋₆alkyl, andC₁₋₆alkoxy, and R² and R³ or R³ and R⁴ together with the atoms to whichthey are attached form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, and wherein the4-8 membered ring is unsubstituted or substituted with a substituentselected from OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy.

In another class of the embodiments, R¹, R², R³ and R⁴ are eachindependently selected from the group consisting of: hydrogen, halogen,—OH, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)NR¹¹R¹², —(CH₂)_(n)NR¹³R¹⁵, and—(CH₂)_(n)SR¹³, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, OH,C₁₋₆alkyl, and C₁₋₆alkoxy, or R² and R³ or R³ and R⁴ together with theatoms to which they are attached form a 4-8 membered ring containing 0-2heteroatoms independently selected from oxygen, sulfur, and N—R¹⁵, andwherein the 4-8 membered ring is unsubstituted or substituted with asubstituent selected from —OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy.

In another class of the embodiments, R¹ is selected from the groupconsisting of: hydrogen, halogen, —OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy,wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy.In a subclass of this subclass, R¹ is selected from the group consistingof: hydrogen, halogen, —OH, —C₁₋₆alkyl optionally substituted withfluoride, and —OC₁₋₆alkyl optionally substituted with fluoride. Inanother subclass of this subclass, R¹ is selected from hydrogen,halogen, and —OCH₃. In another subclass of this subclass, R¹ is hydrogenor —OCH₃. In another subclass of this subclass, R¹ is hydrogen.

In another class of the embodiments, R² is selected from the groupconsisting of: hydrogen, —OH, halogen, —C₁₋₆alkyl optionally substitutedwith fluoride, —OC₁₋₆alkyl optionally substituted with fluoride,hydroxy, and halogen. In a subclass of this class, R² is selected fromhydrogen, —OCH₃, OCH₂CH₃, —OH, —O(CH)(CH₃)₂, CH₂CH₃, —OCH₂CF₃, andfluoride. In another subclass of this subclass, R² is selected fromhydrogen, —OH, —OCH₃, and OCH₂CH₃. In yet another subclass of thissubclass, R² is —OCH₂CH₃.

In another class of the embodiments, R³ is selected from the groupconsisting of: hydrogen, —OH, halogen, —C₁₋₆alkyl optionally substitutedwith fluoride, and —OC₁₋₆alkyl optionally substituted with fluoride. Ina subclass of this class, R³ is selected from hydrogen, halogen, and—OCH₃. In another subclass of this class, R³ is hydrogen or —OCH₃. Inanother subclass of this class, R³ is hydrogen.

In another class of the embodiments, R⁴ is selected from the groupconsisting of: hydrogen, —OH, halogen, —C₁₋₆alkyl optionally substitutedwith fluoride, and —OC₁₋₆alkyl optionally substituted with fluoride. Ina subclass of this class, R⁴ is selected from hydrogen, —OCH₃, OCH₂CH₃,—OH, —O(CH)(CH₃)₂; —CH₂CH₃, —OCH₂CF₃, and fluoride. In another subclassof this class, R⁴ is selected from hydrogen and —OCH₂CH₃. In anothersubclass of this class, R⁴ is hydrogen. In another subclass of thisclass, R⁴ is —OCH₂CH₃.

In another class of the embodiments, R² and R³ are each independentlyselected from the group consisting of: OH, C₁₋₆alkyl, and C₁₋₆alkoxywherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy,or R² and R³ together with the atoms to which they are attached form a4-8 membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R⁵, wherein the 4-8 membered ring is unsubstitutedor substituted with a substituent selected from the group consisting of:OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy. In another class of theembodiments, R² and R³ are each independently selected from the groupconsisting of: —C₁₋₆alkoxy unsubstituted or substituted with one to fivesubstituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R²and R³ together with the atoms to which they are attached form a 4-8membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R¹⁵, wherein the ring is unsubstituted orsubstituted with a substituent selected from the group consisting of:OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy.

In another class of the embodiments, R³ and R⁴ are each independentlyselected from the group consisting of: OH, C₁₋₆alkyl, and C₁₋₆alkoxywherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy,or R³ and R⁴ together with the atoms to which they are attached form a4-8 membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R⁵, wherein the 4-8 membered ring is unsubstitutedor substituted with a substituent selected from the group consisting of:OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy. In another class of theembodiments, R³ and R⁴ are each independently selected from the groupconsisting of: —C₁₋₆alkoxy unsubstituted or substituted with one to fivesubstituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R³and R⁴ together with the atoms to which they are attached form a 4-8membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R⁵, wherein the ring is unsubstituted orsubstituted with a substituent selected from the group consisting of:OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy.

In another class of the embodiments, R¹ and R² are each independentlyselected from the group consisting of: hydrogen, halogen, —OH,—C₁₋₆alkyl, and —C₁₋₆alkoxy, wherein alkyl and alkoxy are unsubstitutedor substituted with one to five substituents selected from halogen, OH,C₁₋₆alkyl, and C₁₋₆alkoxy, and R³ and R⁴ are each independently selectedfrom the group consisting of: —OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy whereinalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R³and R⁴ together with the atoms to which they are attached form a 4-8membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R¹⁵, wherein the 4-8 membered ring isunsubstituted or substituted with a substituent selected from —OH,halogen, C₁₋₆alkyl, and C₁₋₆alkoxy; and pharmaceutically acceptablesalts thereof. In a subclass of this class, R¹ and R² are each hydrogen.In another subclass of this class, R¹ and R² are each hydrogen, and R³and R⁴ form a ring selected from dioxane, piperidine, pyrrolidine,tetrahydropyran, dihydropyran, dihydrofuran, tetrahydrofuran, anddioxolane. In another subclass of this class, R¹ and R² are eachhydrogen, and R³ and R⁴ form a dioxane ring, a dioxolane ring, adihydropyran ring, or a dihydrofuran ring. In another subclass of thisclass, R¹ and R² are each hydrogen, and R³ and R⁴ form a 1,4-dioxanering.

In another class of the embodiments, R¹ and R⁴ are each independentlyselected from the group consisting of: hydrogen, halogen, —OH,—C₁₋₆alkyl, and —C₁₋₆alkoxy wherein alkyl and alkoxy are unsubstitutedor substituted with one to five substituents selected from halogen, OH,C₁₋₆alkyl, and C₁₋₆alkoxy, and R² and R³ are each independently selectedfrom the group consisting of: —OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy whereinalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R²and R³ together with the atoms to which they are attached form a 4-8membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R¹⁵, wherein the 4-8 membered ring isunsubstituted or substituted with a substituent selected from —OH,halogen, C₁₋₆alkyl, and C₁₋₆alkoxy; and pharmaceutically acceptablesalts thereof. In a subclass of this class, R¹ and R⁴ are each hydrogen.In another subclass of this class, R¹ and R⁴ are each hydrogen, and R²and R³ form a ring selected from dioxane, piperidine, pyrrolidine,tetrahydropyran, dihydropyran, dihydrofuran, tetrahydrofuran, anddioxolane. In another subclass of this class, R¹ and R⁴ are eachhydrogen, and R² and R³ form a dioxane ring, a dioxolane ring, adihydropyran ring, or a dihydrofuran ring. In another subclass of thisclass, R¹ and R⁴ are each hydrogen, and R² and R³ form a 1,4-dioxanering.

In another class of the embodiments, R⁵, R⁶ and R⁷ are eachindependently selected from the group consisting of: hydrogen, halogen,—OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents selected fromhalogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R⁵ and R⁶ together with theatoms to which they are attached form a 4-8 membered ring containing 0-2heteroatoms independently selected from oxygen, sulfur, and N—R¹⁵, andwherein the 4-8 membered ring is unsubstituted or substituted with asubstituent selected from —OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy. In asubclass of this class, R⁵ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl optionally substituted with fluoride, —OC₁₋₆alkyloptionally substituted with fluoride, hydroxy, and halogen. In asubclass of this subclass, R⁵ is selected from hydrogen, —OCH₃, —CH₃,—CH₂CH₃, —CF₃, fluoride and chloride. In another subclass of thissubclass, R⁵ is selected from hydrogen, —CH₃, chloride, and fluoride. Inanother subclass of this subclass, R⁵ is selected from hydrogen andfluoride. In another subclass of this subclass, R⁵ is hydrogen. Inanother subclass of this subclass, R⁵ is fluoride.

In another class of the embodiments, R⁵, R⁶ and R⁷ are eachindependently selected from the group consisting of: hydrogen, halogen,—OH, —C₁₋₆alkyl, and —C₁₋₆alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents selected fromhalogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy, or R⁵ and R⁶ or R⁶ and R⁷together with the atoms to which they are attached form a 4-8 memberedring containing 0-2 heteroatoms independently selected from oxygen,sulfur, and N—R¹⁵, and wherein the 4-8 membered ring is unsubstituted orsubstituted with a substituent selected from —OH, halogen, C₁₋₆alkyl,and C₁₋₆alkoxy. In a subclass of this class, R⁵ is selected from thegroup consisting of: hydrogen, —C₁₋₆alkyl optionally substituted withfluoride, —OC₁₋₆alkyl optionally substituted with fluoride, hydroxy, andhalogen. In a subclass of this subclass, R⁵ is selected from hydrogen,—OCH₃, —CH₃, —CH₂CH₃, —CF₃, fluoride and chloride. In another subclassof this subclass, R⁵ is selected from hydrogen, —CH₃, chloride, andfluoride. In another subclass of this subclass, R⁵ is selected fromhydrogen and fluoride. In another subclass of this subclass, R⁵ ishydrogen. In another subclass of this subclass, R⁵ is fluoride.

In another class of the embodiments, R⁶ is selected from the groupconsisting of: hydrogen, —C₁₋₆alkyl optionally substituted withfluoride, —OC₁₋₆alkyl optionally substituted with fluoride, hydroxy, andhalogen. In a subclass of this class, R⁶ is selected from hydrogen,—OCH₃, OCH₂CH₃, —OH, —O(CH)(CH₃)₂, —CH₂CH₃, —OCH₂CF₃, and fluoride. Inanother subclass of this class, R⁶ is selected from hydrogen, —OCH₃,—CH₃, —CH₂CH₃, —CF₃, fluoride and chloride. In another subclass of thisclass, R⁶ is selected from hydrogen, —CH₃, fluoride and chloride. Inanother subclass of this class, R⁶ is hydrogen. In another subclass ofthis class, R⁶ is selected from —CH₃, fluoride and chloride.

In another class of the embodiments, R⁷ is selected from the groupconsisting of: hydrogen, halogen, —C₁₋₆alkyl optionally substituted withfluoride, —OC₁₋₆alkyl optionally substituted with fluoride, hydroxy, andhalogen. In a subclass of this class, R⁷ is selected from hydrogen, andfluoride. In another subclass of this class, R⁷ is hydrogen. In anothersubclass of this class, R⁷ is fluoride.

In another class of the embodiments, R⁵ and R⁶ are each independentlyselected from the group consisting of: OH, C₁₋₆alkyl, and C₁₋₆alkoxywherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy,and R⁵ and R⁶ together with the atoms to which they are attached form a4-8 membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R⁵, wherein the 4-8 membered ring is unsubstitutedor substituted with a substituent selected from the group consisting of:OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy. In another class of theembodiments, R⁵ and R⁶ are each independently selected from the groupconsisting of: —C₁₋₆alkoxy unsubstituted or substituted with one to fivesubstituents selected from halogen; OH; C₁₋₆alkyl; and C₁₋₆alkoxy; or R⁵and R⁶ together with the atoms to which they are attached form a 4-8membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R⁵, wherein the ring is unsubstituted orsubstituted with a substituent selected from the group consisting of:OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy. In a subclass of this class, R⁷is hydrogen. In another subclass of this class, R⁷ is hydrogen, and R⁵and R⁶ form a ring selected from dioxane, piperidine, pyrrolidine,tetrahydropyran, dihydropyran, dihydrofuran, tetrahydrofuran, anddioxolane. In another subclass of this class, R⁷ is hydrogen, and R⁵ andR⁶ form a dioxane ring, a dioxolane ring, a dihydropyran ring, or adihydrofuran ring. In another subclass of this class, R⁷ is hydrogen,and R⁵ and R⁶ form a 1,4-dioxane ring.

In another class of the embodiments, R⁶ and R⁷ are each independentlyselected from the group consisting of: OH, C₁₋₆alkyl, and C₁₋₆alkoxywherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy,or R⁶ and R⁷ together with the atoms to which they are attached form a4-8 membered ring containing 0-2 heteroatoms independently selected fromoxygen, sulfur, and N—R¹⁵, wherein the 4-8 membered ring isunsubstituted or substituted with a substituent selected from the groupconsisting of: OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy. In another classof the embodiments, R⁶ and R⁷ are each independently selected from thegroup consisting of: —C₁₋₆alkoxy unsubstituted or substituted with oneto five substituents selected from halogen; OH; C₁₋₆alkyl; andC₁₋₆alkoxy; and R⁶ and R⁷ together with the atoms to which they areattached form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, sulfur, and N—R¹⁵, wherein the ringis unsubstituted or substituted with a substituent selected from thegroup consisting of: OH, halogen, C₁₋₆alkyl, and C₁₋₆alkoxy. In asubclass of this class, R⁵ is hydrogen. In another subclass of thisclass, R⁵ is hydrogen, and R⁶ and R⁷ form a ring selected from dioxane,piperidine, pyrrolidine, tetrahydropyran, dihydropyran, dihydrofuran,tetrahydrofuran, and dioxolane. In another subclass of this class, R⁵ ishydrogen, and R⁶ and R⁷ form a dioxane ring, a dioxolane ring, adihydropyran ring, or a dihydrofuran ring. In another subclass of thisclass, R⁵ is hydrogen, and R⁶ and R⁷ form a 1,4-dioxane ring.

In another class of the embodiments, R⁵ is selected from the groupconsisting of: hydrogen, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, and—C₃₋₆cycloalkyl, wherein alkyl, alkoxy and cycloalkyl are unsubstitutedor substituted with one to five substituents selected from halogen and—OH. In a subclass of this class, R⁹ is hydrogen. In another subclass ofthis class, R⁸ is C₁₋₆alkyl. In another subclass of this class, R⁸ isselected from the group consisting of: halogen and —C₁₋₆alkoxy. In asubclass of this subclass, R⁸ is halogen. In another subclass of thissubclass, R¹ is selected from the group consisting of: bromide,chloride, fluoride and iodide. In another subclass of this subclass, R⁸is bromide.

In another class of the embodiments, each R⁹ is independently selectedfrom the group consisting of: hydrogen, —CF₃, —OH, —CN, C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)NR¹⁷R¹⁸, -a 5-10 membered aromatic monocyclic orbicyclic heterocyclic ring, and phenyl, wherein alkyl, alkoxy, theheterocyclic ring and phenyl are unsubstituted or substituted with oneor more substituents selected from C₁₋₆alkyl, —OH, phenyl, C₁₋₆alkoxy,—CF₃, —CN, and halogen. In a subclass of this class, both R⁹ arehydrogen. In another subclass of this class, one R⁹ is hydrogen and oneR⁹ is C₁₋₆alkyl. In yet another subclass of this class, one R⁹ ishydrogen and one R⁹ is C₁₋₆alkyl substituted with —OH or phenyl.

In another class of the embodiments, each R¹⁰ is independently selectedfrom the group consisting of: —(CH₂)_(n)halogen, —(CH₂)_(n)CN,—(CH₂)_(n)NO₂, —(CH₂)_(n)OR¹², —C₂₋₆alkene-CO₂R¹², —(CH₂)_(n)COR¹³,—(CH₂)_(n)CO₂R¹², —(CH₂)_(n)C(O)NR¹¹R¹², —(CH₂)_(n)CONR¹¹COR¹³,—(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R¹², —(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹²)₂,—(CH₂)_(n)NR¹¹R¹², —(CH₂)_(n)NR¹¹C(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹C(O)R¹³,—(CH₂)_(n)OC(O)NR¹¹R¹², —(CH₂)_(n)NR¹¹CO₂R¹², —(CH₂)_(n)NR¹¹SO₂R¹³,—(CH₂)_(n)SO₂NR¹¹R¹², —(CH₂)_(n)SO₂R¹³, —(CH₂)_(n)SO₃H,—(CH₂)_(n)PO₂R¹³, —(CH₂)_(n)PO₃H, —C₁₋₆alkyl, —(CH₂)_(n)aryl,—(CH₂)_(n)heteroaryl, —(CH₂)_(n)heterocycloalkyl, and—(CH₂)_(n)C₃₋₈cycloalkyl, wherein alkyl is substituted with one to fivesubstituents selected from —C₁₋₆alkyl, oxo, halogen, —C₁₋₆alkoxy,—(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, wherein alkene and —(CH₂)_(n) are unsubstituted orsubstituted with one to five substituents selected from —C₁₋₆alkyl, oxo,halogen, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃,—(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and—(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, and wherein cycloalkyl,heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substitutedwith one to five substituents independently selected from oxo, halogen,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl.

In another class of the embodiments, each R¹⁰ is independently selectedfrom the group consisting of: —(CH₂)_(n)halogen, —C₂₋₆alkene-CO₂R¹²,—(CH₂)_(n)COR¹³, —(CH₂)_(n)CO₂R¹², —(CH₂)₃C(O)NR¹¹R¹²,—(CH₂)_(n)CONR¹¹COR¹³, —(CH₂)_(n)C(O)NR¹¹(CH₂)_(n)CO₂R²,—(CH₂)_(n)C(O)NR¹¹CH(CO₂R¹²)₂, and —(CH₂)_(n)heteroaryl, wherein alkeneand —(CH₂)_(n) are unsubstituted or substituted with one to fivesubstituents selected from —C₁₋₆alkyl, oxo, halogen, —C₁₋₆alkoxy,—(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, and wherein heteroaryl is unsubstituted or substitutedwith one to five substituents independently selected from oxo, halogen,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl.

In another class of the embodiments, each R¹⁰ is independently selectedfrom the group consisting of: halogen, —C₂₋₆alkene-CO₂H,—C(O)C₂₋₈heterocycloalkyl, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₈alkyl,—(CH₂)_(n)CO₂aryl, —(CH₂)_(n)CO₂C₂₋₈ heterocycloalkyl, —(CH₂)_(n)CONH₂,—(CH₂)_(n)CONHC₁₋₈alkyl, —(CH₂)_(n)CON(C₁₋₈alkyl)₂,—(CH₂)_(n)CONHC₃₋₈cycloalkyl, —(CH₂)_(n)CONHaryl,—(CH₂)_(n)CONH(CH₂)₁₋₆OH, —(CH₂)_(n)CONHC₂₋₈heteroaryl,—(CH₂)_(n)C(O)NHCH₂CO₂C₁₋₈alkyl, —(CH₂)_(n)C(O)N(C₁₋₈alkyl)CH₂CO₂H,—(CH₂)_(n)C(O)NHCH₂CO₂H, —C(O)NHCH(CO₂CH₂aryl)₂,—C(O)NHCH(CO₂C₁₋₈alkyl)₂, and —(CH₂)_(n)heteroaryl, wherein alkyl,cycloalkyl, heterocycloalkyl, aryl, alkene, heteroaryl and —(CH₂)_(n)are unsubstituted or substituted with one to eight substituents selectedfrom —C₁₋₆alkyl, oxo, halogen, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl.

In another class of the embodiments, each R¹⁰ is independently selectedfrom the group consisting of: Cl, —CH═CHCO₂H, —C(O)morpholine,—C(O)pyrrolidine, —C(O)piperidine, —CO₂H, —CO₂CH₂phenyl, —CO₂CH₃,—(CH₂)₂CO₂H, —CO₂tetrahydropyran, —CONH₂, —CONHCH₃, —CONHCH₂CH₃,—CON(CH₂CH₃)₂, —CON(CH₃)₂, —CONHCH(CH₃)₂, —CONHcyclopropyl, —CONHphenyl,—C(O)NHcyclopentyl, —C(O)NH(CH₂)₁₋₆OH, —C(O)NHtetrahydropyran,—CONHCH₂CO₂H, —CON(CH₃)CH₂CO₂H, —CONHCOC(CH₃)₃,—C(O)NHCH(CO₂CH₂phenyl)₂, —C(O)NHCH(CO₂CH₂CH₃)₂, and tetrazole, whereinthe alkyl, alkene, cycloalkyl, heterocycloalkyl, aryl, and heteroarylsubstituents and —(CH₂)_(n) are unsubstituted or substituted with one toeight substituents selected from —C₁₋₆alkyl, oxo, halogen, —C₁₋₆alkoxy,—(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl.

In another class of the embodiments, each R¹⁰ is independently selectedfrom the group consisting of: —(CH₂)_(n)OR¹², —(CH₂)_(n)COR¹³,—(CH₂)_(n)CO₂R², and —(CH₂)_(n)C(O)NR¹¹R¹², wherein —(CH₂)_(n) isunsubstituted or substituted with one to five substituents selected from—C₁₋₆alkyl, oxo, halogen, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl. In a subclass of thisclass, at least one R¹⁰ is —(CH₂)_(n)CO₂H. In a subclass of thissubclass, R¹⁰ is —CO₂H. In another subclass of this class, each R¹⁰ isindependently selected from the group consisting of: —OCH₃, —CO₂H;—CO₂CH₃, —C(O)-pyrrolidine, —C(O)N(H)cyclopentyl, —C(O)N(H)CH₃,—C(O)N(H)CH₂(CH₃)₂, —C(O)N(H)CH₂CH₃, and —C(O)N(CH₂CH₃)₂, wherein thealkyl, cycloalkyl and heterocycloalkyl substituents are unsubstituted orsubstituted with one to eight substituents selected from —C₁₋₆alkyl,oxo, halogen, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃,—(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and—(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents independently selected fromhalogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl. In another subclass ofthis class, each R¹⁰ is independently selected from the group consistingof: —OCH₃, —CO₂H, —CO₂CH₃, —C(O)pyrrolidine, —CON(H)CH₂(CH₃)₂,—CON(H)CH₂CH₃, and —CON(CH₂CH₃)₂.

In another class of the embodiments, each R¹¹ and R¹² is independentlyhydrogen or R¹³, or R¹¹ and R¹² together with the nitrogen to which theyare attached form a 4-8 membered heterocyclic ring containing 0-2additional heteroatoms selected from oxygen, sulfur, and NR¹⁵, andwherein the 4-8 membered heterocyclic ring is unsubstituted orsubstituted with one to five substituents independently selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl.

In another class of the embodiments, each R¹¹ and R¹² is independentlyselected from the group consisting of: hydrogen, —C₁₋₈alkyl,—(CH₂)_(n)OH, —(CH₂)_(n)C₃₋₈cycloalkyl, —(CH₂)_(n)C₂₋₈ heterocycloalkyl,—(CH₂)_(n)aryl, and —(CH₂)_(n)heteroaryl, wherein alkyl, cycloalkyl,heterocycloalkyl, and —(CH₂)_(n) are unsubstituted or substituted withone to eight substituents selected from oxo, halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, and wherein aryl and heteroaryl are unsubstituted orsubstituted with one to eight substituents independently selected fromhalogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl, or R¹¹ and R¹² together with thenitrogen to which they are attached form a 4-8 membered heterocyclicring containing 0-2 additional heteroatoms selected from oxygen, sulfur,and NR¹⁵, and wherein the 4-8 membered heterocyclic ring isunsubstituted or substituted with one to five substituents independentlyselected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH,—(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H,—(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl andalkoxy are unsubstituted or substituted with one to five substituentsselected from halogen, —OH, —SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl.

In another class of the embodiments, each R¹¹ and R¹² is independentlyselected from the group consisting of: hydrogen, —C₁₋₈alkyl,—(CH₂)_(n)OH, —(CH₂)_(n)C₃₋₈cycloalkyl, and —(CH₂)_(n)C₂₋₈heterocycloalkyl, wherein alkyl, cycloalkyl, heterocycloalkyl, and—(CH₂)_(n) are unsubstituted or substituted with one to eightsubstituents selected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,—(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, or R¹¹ and R¹² together with the nitrogen to which theyare attached form a 4-8 membered heterocyclic ring containing 0-2additional heteroatoms selected from oxygen, sulfur, and NR¹⁵, andwherein the 4-8 membered heterocyclic ring is unsubstituted orsubstituted with one to five substituents independently selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl. In a subclass of this class, R¹² isselected from cyclopentyl, —(CH₂)_(n)OH, tetrahydropyran, unsubstitutedor substituted with one to five substituents independently selected fromoxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene. In a subclass of this subclass, R¹² isselected from cyclopentyl, —(CH₂)_(n)OH, tetrahydropyran, unsubstitutedor substituted with one to five substituents independently selected from—(CH₂)_(n)OH, and —(CH₂)_(n)CO₂H.

In another class of the embodiments, each R¹³ is independently selectedfrom the group consisting of: —C₁₋₈alkyl, —(CH₂)_(n)OH,—(CH₂)_(n)C₃₋₅cycloalkyl, —(CH₂)_(n)C₂₋₈ heterocycloalkyl,—(CH₂)_(n)aryl, and —(CH₂)_(n)heteroaryl, wherein alkyl, cycloalkyl,heterocycloalkyl, and —(CH₂)_(n) are unsubstituted or substituted withone to eight substituents selected from oxo, halogen, —C₁₋₆alkyl,—C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl, and wherein aryl and heteroaryl are unsubstituted orsubstituted with one to eight substituents independently selected fromhalogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —(CH₂)_(n)OH, —(CH₂)_(n)CN,—(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H, —(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl,and —(CH₂)_(n)CO₂C₂₋₆alkene, and alkyl and alkoxy are unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—SO₃H, —CO₂H, and —CO₂C₁₋₆alkyl. In a subclass of this class, R¹³ isselected from piperidine and tetrahydropyran, wherein piperidine, andtetrahydropyran are unsubstituted or substituted with one to eightsubstituents selected from oxo, halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy,—(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene. Ina subclass of this subclass, R¹³ is selected from piperidine andtetrahydropyran, wherein piperidine, and tetrahydropyran areunsubstituted or substituted with one to eight substituents selectedfrom —(CH₂)_(n)OH, and —(CH₂)_(n)CO₂H.

In another class of the embodiments, each R¹⁴ is independently selectedfrom the group consisting of: —C₁₋₆alkyl, —(CH₂)_(n)C₃₋₈cycloalkyl,—(CH₂)_(n)C₂₋₈ heterocycloalkyl, —(CH₂)_(n)aryl, and—(CH₂)_(n)heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl are unsubstituted or substituted with one to fivesubstituents independently selected from —OH, oxo, halogen, —CN,—(CH₂)_(n)CO₂H, —SO₃H, C₁₋₆alkyl, and C₁₋₆alkoxy, and alkyl and alkoxyare unsubstituted or substituted with one to five substituents selectedfrom halogen, —CO₂H, and —SO₃H.

In yet another class of the embodiments, each R¹⁴ is independentlyselected from the group consisting of: (1) —C₁₋₆alkyl, unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—CO₂H, and —SO₃H, (2) —(CH₂)_(n)C₃₋₈cycloalkyl, unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,—CO₂H, and —SO₃H, (3) —(CH₂)_(n)C₂₋₈ heterocycloalkyl, unsubstituted orsubstituted with one to five substituents selected from halogen, —OH,oxo, —C₁₋₆alkyl, C₁₋₆alkoxy, and —(CH₂)_(n)CO₂H, and alkyl and alkoxyare unsubstituted or substituted with one to five halogens, (4)—(CH₂),aryl, unsubstituted or substituted with one to five substituentsselected from —OH, halogen, —CN, —CO₂H, —SO₃H, C₁-C₆alkyl, andC₁₋₆alkoxy, and alkyl and alkoxy are unsubstituted or substituted withone to five substituents selected from halogen, —OH, —CO₂H, and —SO₃H,and (5) —(CH₂)_(n)heteroaryl, unsubstituted or substituted with one tofive substituents independently selected from —OH, halogen, —CN, —CO₂H,—SO₃H, C₁₋₆alkyl, and C₁₋₆alkoxy, and alkyl and alkoxy are unsubstitutedor substituted with one to five substituents selected from halogen,—CO₂H, and —SO₃H.

In another class of the embodiments, each R¹⁴ is independently selectedfrom the group consisting of: (1) —(CH₂)_(n)C₃₋₈cycloalkyl unsubstitutedor substituted with one to five substituents selected from halogen,hydrogen, —OH, —CO₂H, and —SO₃H, and (2) —(CH₂)_(n)C₂₋₈ heterocycloalkylunsubstituted or substituted with one to five substituents selected fromhalogen, —OH, oxo, —C₁₋₆alkyl, C₁₋₆alkoxy, and —(CH₂)_(n)CO₂H, and alkyland alkoxy are unsubstituted or substituted with one to five halogens.

In another class of the embodiments, each R¹⁵ is independently selectedfrom the group consisting of: hydrogen, —C₁₋₆alkyl, —C₃₋₈cycloalkyl,—SO₂R⁴, —COR¹⁴, —CO₂R⁴, and —CO₂H, wherein alkyl and cycloalkyl areunsubstituted or substituted with one to five substituents selected fromhalogen, —OH, and —(CH₂)_(n)CO₂H.

In another class of the embodiments, R¹⁶ is selected from the groupconsisting of: hydrogen, —CF₃, —OH, —CN, —C₁₋₆alkyl, —C₁₋₆alkoxy,—(CH₂)_(n)C₃₋₈cycloalkyl, —(CH₂)_(n)NR¹⁷R¹⁸, -a 5-10 membered aromaticmonocyclic or bicyclic heterocyclic ring, and phenyl, wherein alkyl,alkoxy, cycloalkyl, the heterocyclic ring and phenyl are unsubstitutedor substituted with one or more substituents selected from C₁₋₆alkyl,—OH, phenyl, C₁₋₆alkoxy, —CF₃, —CN, and halogen. In a subclass of thisclass, R¹⁶ is selected from the group consisting of: hydrogen, —OH,—C₁₋₆alkyl unsubstituted or substituted with —OH or phenyl, and—C₁₋₆alkoxy. In another subclass of this class, R¹⁶ is hydrogen. Inanother subclass of this class, R¹⁶ is —OH.

In another class of the embodiments, each m is independently 1, 2, 3 or4. In a subclass of this class, m is 1 or 2. In another subclass of thisclass, m is 1. In another subclass of this class, m is 2.

each n is independently 0, 1, 2, or 3.

In another class of the embodiments, each n is independently 0, 1, 2, 3,4, 5, 6, 7 or 8. In a subclass of this class, each n is independently 0,1, 2, 3, 4, 5 or 6. In a subclass of this class, n is 0, 1, or 2. Inanother subclass of this class, n is 0. In another subclass of thisclass, n is 1. In another subclass of this class, n is 2. In anothersubclass of this class, n is 3. In another subclass of this class, n is4. In another subclass of this class, n is 5. In another subclass ofthis class, n is 6. In another class of the embodiments, each p isindependently 0, 1, 2, 3 or 4. In a subclass of this class, p is 0. Inanother subclass of this class, p is 1. In another subclass of thisclass, p is 2.

In another embodiment, the compound of formula I is selected from:

-   (1)    3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (2)    3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (3)    3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (4)    3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (5)    3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic    acid,-   (6)    3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic    acid,-   (7)    1-(7-methoxy-2-naphthyl)-4-{[1-(3-methoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperazine,-   (8)    3-(4-{[1-(3-methoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic    acid,-   (9)    methyl-2-(4-{[1-(3-methoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoate,-   (10)    6-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (11)    3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N-isopropyl-1-naphthamide,-   (12)    1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-[4-(1-pyrrolidinylcarbonyl)-2-naphthyl]piperazine,-   (13)    3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N-ethyl-1-naphthamide,-   (14)    3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N,N-diethyl-1-naphthamide,-   (15)    1-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-[3-(1-pyrrolidinylcarbonyl)-2-naphthyl]piperazine,-   (16)    3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N,N-diethyl-2-naphthamide,-   (17)    3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N-ethyl-2-naphthamide,-   (18)    3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-N-isopropyl-2-naphthamide,-   (19)    3-(4-{[2-(2,4-difluorophenyl)-1-(3-ethoxyphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic    acid,-   (20)    3-(4-{[1-(3-hydroxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (21)    3-(4-{[1-(3-ethoxyphenyl)-2-phenyl-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (22)    3-(4-{[2-(4-chlorophenyl)-1-(3-ethoxyphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (23)    3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic    acid,-   (24)    3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (25)    3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (26)    3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic    acid,-   (27)    3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoic    acid,-   (28)    3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoic    acid,-   (29)    3-(1-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-piperidinyl)-1-naphthoic    acid,-   (30)    3-(1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-piperidinyl)-1-naphthoic    acid, and-   (31)    3-(1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-hydroxy-4-piperidinyl)-1-naphthoic    acid;    or a pharmaceutically acceptable salt thereof.

In a class of this embodiment, the compound of formula I is selectedfrom:3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; or a pharmaceutically acceptable salt thereof. In another class ofthis embodiment, the compound of formula I is selected from:3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; or a pharmaceutically acceptable salt thereof. In another class ofthis embodiment, the compound of formula I is selected from:3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; or a pharmaceutically acceptable salt thereof. In another class ofthis embodiment, the compound of formula I is selected from:3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; or a pharmaceutically acceptable salt thereof. In another class ofthis embodiment, the compound of formula I is selected from:3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; or a pharmaceutically acceptable salt thereof.

In another class of the embodiments, the pharmaceutically acceptablesalt is a trifluoroacetic acid salt. In another class of theembodiments, the pharmaceutically acceptable salt is a hydrochloric acidsalt.

The compounds of formula I, II and III are effective as cholecystokininreceptor ligands and are particularly effective as selective ligands ofthe cholecystokinin-1 receptor. They are therefore useful for thetreatment and/or prevention of disorders responsive to the modulation ofthe cholecystokinin-1 receptor, such as obesity, diabetes, andobesity-related disorders. More particularly, the compounds of formulaI, II and III are selective cholecystokinin-1 receptor (CCK-1R) agonistsuseful for the treatment of disorders responsive to the activation ofthe cholecystokinin-1 receptor, such as obesity, diabetes, as well asthe treatment of gallstones.

One aspect of the present invention provides a method for the treatmentor prevention of disorders, diseases or conditions responsive to themodulation of the cholecystokinin-1 receptor in a subject in needthereof which comprises administering to the subject a therapeuticallyor prophylactically effective amount of a compound of formula I, II orIII, or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for thetreatment or prevention of obesity, diabetes, or an obesity relateddisorder in a subject in need thereof which comprises administering tosaid subject a therapeutically or prophylactically effective amount of acholecystokinin-1 receptor agonist of the present invention. Anotheraspect of the present invention provides a method for the treatment orprevention of obesity in a subject in need thereof which comprisesadministering to the subject a therapeutically or prophylacticallyeffective amount of a compound of formula I, II or III, or apharmaceutically acceptable salt thereof. Another aspect of the presentinvention provides a method for reducing food intake in a subject inneed thereof which comprises administering to the subject atherapeutically or prophylactically effective amount of a compound offormula I, II or III, or a pharmaceutically acceptable salt thereof.Another aspect of the present invention provides a method for increasingsatiety in a subject in need thereof which comprises administering tothe subject a therapeutically or prophylactically effective amount of acompound of formula I, II or III, or a pharmaceutically acceptable saltthereof. Another aspect of the present invention provides a method forreducing appetite in a subject in need thereof which comprisesadministering to the subject a therapeutically or prophylacticallyeffective amount of a compound of formula I, II or III, or apharmaceutically acceptable salt thereof. Another aspect of the presentinvention provides a method for delaying gastric emptying in a subjectin need thereof which comprises administering to the subject atherapeutically or prophylactically effective amount of a compound offormula I, II or III, or a pharmaceutically acceptable salt thereof.Another aspect of the present invention provides a method for thetreatment or prevention of bulimia nervosa in a subject in need thereofwhich comprises administering to the subject a therapeutically orprophylactically effective amount of a compound of formula I, II or III,or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for thetreatment or prevention of diabetes mellitus in a subject in needthereof comprising administering to the subject a therapeutically orprophylactically effective amount of a compound of formula I, II or III,or a pharmaceutically acceptable salt thereof. Another aspect of thepresent invention provides a method for the treatment or prevention ofdyslipidemia in a subject in need thereof which comprises administeringto the subject a therapeutically or prophylactically effective amount ofa compound of formula I, II or III, or a pharmaceutically acceptablesalt thereof.

Another aspect of the present invention provides a method for thetreatment or prevention of tardive dyskinesia in a subject in needthereof which comprises administering to said subject a therapeuticallyor prophylactically effective amount of a cholecystokinin-1 receptoragonist of the present invention.

Another aspect of the present invention provides a method for thetreatment or prevention of an obesity-related disorder selected from thegroup consisting of overeating, binge eating, hypertension, elevatedplasma insulin concentrations, insulin resistance, hyperlipidemia,endometrial cancer, breast cancer, prostate cancer, colon cancer, kidneycancer, osteoarthritis, obstructive sleep apnea, heart disease, abnormalheart rhythms and arrythmias, myocardial infarction, congestive heartfailure, coronary heart disease, sudden death, stroke, polycystic ovarydisease, craniopharyngioma, metabolic syndrome, insulin resistancesyndrome, sexual and reproductive dysfunction, infertility,hypogonadism, hirsutism, obesity-related gastro-esophageal reflux,Pickwickian syndrome, inflammation, systemic inflammation of thevasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia,lower back pain, gallbladder disease, gout, constipation, irritablebowel syndrome, inflammatory bowel syndrome, cardiac hypertrophy, leftventricular hypertrophy, in a subject in need thereof which comprisesadministering to the subject a therapeutically or prophylacticallyeffective amount of a compound of formula I, II or III, or apharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for thetreatment or prevention of

cognitive and memory deficiency, including the treatment of Alzheimer'sdisease, in a subject in need thereof which comprises administering tothe subject a therapeutically or prophylactically effective amount of acompound of formula I, II or III, or a pharmaceutically acceptable saltthereof.

Another aspect of the present invention provides a method for thetreatment or prevention of

pain in a subject in need thereof which comprises administering to thesubject a therapeutically or prophylactically effective amount of acompound of formula I, II or III, or a pharmaceutically acceptable saltthereof.

Another aspect of the present invention provides a method for thetreatment or prevention of

cholelithiasis (gallstones) in a subject in need thereof which comprisesadministering to the subject a therapeutically or prophylacticallyeffective amount of a compound of formula I, II or III, or apharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a method for thetreatment or prevention of

cholecystitis (inflammation of the gallbladder) in a subject in needthereof which comprises administering to the subject a therapeuticallyor prophylactically effective amount of a compound of formula I, II orIII, or a pharmaceutically acceptable salt thereof.

The present invention also relates to methods for treating or preventingobesity by administering a cholecystokinin-1 receptor agonist of thepresent invention in combination with a therapeutically orprophylactically effective amount of another agent known to be useful totreat or prevent the condition. The present invention also relates tomethods for treating or preventing diabetes by administering thecholecystokinin-1 receptor agonist of the present invention incombination with a therapeutically or prophylactically effective amountof another agent known to be useful to treat or prevent the condition.The present invention also relates to methods for treating or preventingobesity related disorders by administering the cholecystokinin-1receptor agonist of the present invention in combination with atherapeutically or prophylactically effective amount of another agentknown to be useful to treat or prevent the condition.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of formula I, II or III and apharmaceutically acceptable carrier. Yet another aspect of the presentinvention relates to the use of a compound of formula I, II or III forthe manufacture of a medicament useful for the treatment or prevention,or suppression of a disease mediated by the cholecystokinin-1 receptorin a subject in need thereof. Yet another aspect of the presentinvention relates to the use of a cholecystokinin-1 agonist of thepresent invention for the manufacture of a medicament useful for thetreatment or prevention, or suppression of a disease mediated by thecholecystokinin-1 receptor, wherein the disease is selected from thegroup consisting of obesity, diabetes and an obesity-related disorder ina subject in need thereof. Yet another aspect of the present inventionrelates to the use of a cholecystokinin-1 agonist of the presentinvention for the manufacture of a medicament useful for the treatmentor prevention of gallstones in a subject in need thereof. Yet anotheraspect of the present invention relates to the use of acholecystokinin-1 agonist of the present invention for the manufactureof a medicament useful for the treatment or prevention of dyslipidemiain a subject in need thereof. Yet another aspect of the presentinvention relates to the use of a cholecystokinin-1 agonist of thepresent invention for the manufacture of a medicament useful for thetreatment or prevention of bulimia nervosa in a subject in need thereof.Yet another aspect of the present invention relates to the use of acholecystokinin-1 agonist of the present invention for the manufactureof a medicament useful for the treatment or prevention of constipationin a subject in need thereof. Yet another aspect of the presentinvention relates to the use of a cholecystokinin-1 agonist of thepresent invention for the manufacture of a medicament useful for thetreatment or prevention of irritable bowel syndrome in a subject in needthereof.

Yet another aspect of the present invention relates to the use of atherapeutically effective amount of a cholecystokinin-1 receptor agonistof formula I, II or III, or a pharmaceutically acceptable salt thereof,and a therapeutically effective amount of an agent selected from thegroup consisting of an insulin sensitizer, an insulin mimetic, asulfonylurea, an α-glucosidase inhibitor, a dipeptidyl peptidase 4(DPP-4 or DP-IV) inhibitor, a glucagons like peptide 1 (GLP-1) agonist,a HMG-CoA reductase inhibitor, a serotonergic agent, a β3-adrenoreceptoragonist, a neuropeptide Y1 antagonist, a neuropeptide Y2 agonist, aneuropeptide Y5 antagonist, a pancreatic lipase inhibitor, a cannabinoidCB₁ receptor antagonist or inverse agonist, a melanin-concentratinghormone receptor antagonist, a melanocortin 4 receptor agonist, abombesin receptor subtype 3 agonist, a ghrelin receptor antagonist, PYY,PYY₃₋₃₆, and a NK-1 antagonist, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament useful for the treatment,control, or prevention of obesity, diabetes or an obesity-relateddisorder in a subject in need of such treatment. Yet another aspect ofthe present invention relates to the use of a therapeutically effectiveamount of a cholecystokinin-1 receptor agonist of formula I, II or III,and pharmaceutically acceptable salts and esters thereof, and atherapeutically effective amount of an agent selected from the groupconsisting of an insulin sensitizer, an insulin mimetic, a sulfonylurea,an α-glucosidase inhibitor, a dipeptydyl peptidase 4 inhibitor, aglucagon-like peptide 1 agonist, a HMG-CoA reductase inhibitor, aserotonergic agent, a β3-adrenoreceptor agonist, a neuropeptide Y1antagonist, a neuropeptide Y2 agonist, a neuropeptide Y5 antagonist, apancreatic lipase inhibitor, a cannabinoid CB₁ receptor antagonist orinverse agonist, a melanin-concentrating hormone receptor antagonist, amelanocortin 4 receptor agonist, a bombesin receptor subtype 3 agonist,a ghrelin receptor antagonist, PYY, PYY₃₋₃₆, and a NK-1 antagonist, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for treatment or prevention of obesity, diabetes or anobesity-related disorder which comprises an effective amount of acholecystokinin-1 receptor agonist of formula I, II or III and aneffective amount of the agent, together or separately. Yet anotheraspect of the present invention relates to a product containing atherapeutically effective amount of a cholecystokinin-1 receptor agonistof formula I, II or III, or a pharmaceutically acceptable salt thereof;and a therapeutically effective amount of an agent selected from thegroup consisting of an insulin sensitizer, an insulin mimetic, asulfonylurea, an α-glucosidase inhibitor, a HMG-CoA reductase inhibitor,a serotonergic agent, a β3-adrenoreceptor agonist, a neuropeptide Y1antagonist, a neuropeptide Y2 agonist, a neuropeptide Y5 antagonist, apancreatic lipase inhibitor, a cannabinoid CB₁ receptor antagonist orinverse agonist, a melanocortin 4 receptor agonist, amelanin-concentrating hormone receptor antagonist, a bombesin receptorsubtype 3 agonist, a ghrelin receptor antagonist, PYY, PYY₃₋₃₆, and aNK-1 antagonist, or a pharmaceutically acceptable salt thereof, as acombined preparation for simultaneous, separate or sequential use inobesity, diabetes, or an obesity-related disorder.

The compounds of formula I, II and III can be provided in kit. Such akit typically contains an active compound in dosage forms foradministration. A dosage form contains a sufficient amount of activecompound such that a beneficial effect can be obtained when administeredto a patient during regular intervals, such as 1, 2, 3, 4, 5 or 6 timesa day, during the course of 1 or more days. Preferably, a kit containsinstructions indicating the use of the dosage form for weight reduction(e.g., to treat obesity) and the amount of dosage form to be taken overa specified time period.

Throughout the instant application, the following terms have theindicated meanings:

The term “alkyl”, as well as other groups having the prefix “alk”, suchas alkoxy, alkanoyl, means carbon chains of the designated length whichmay be in a straight or branched configuration, or combinations thereof.Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, n-pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl,1,1-dimethylpropyl, 2,2-dimethylpropyl, n-hexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl,2-ethylbutyl, 3-ethylbutyl, 1,1-dimethyl butyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl,4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl,3-ethylpentyl, 4-ethylpentyl, 1-propylbutyl, 2-propylbutyl,3-propylbutyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl,1,3-dimethylpentyl, 1,4-dimethylpentyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl,3,4-dimethylpentyl, 4,4-dimethylpentyl, 1-methyl-1-ethylbutyl,1-methyl-2-ethylbutyl, 2-methyl-2-ethylbutyl, 1-ethyl-2-methylbutyl,1-ethyl-3-methylbutyl, 1,1-diethylpropyl, n-octyl, n-nonyl, and thelike.

The term “alkenyl” means carbon chains which contain at least onecarbon-carbon double bond, and which may be linear or branched orcombinations thereof. Examples of alkenyl include vinyl, allyl,isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like.

The term “alkynyl” means carbon chains which contain at least onecarbon-carbon triple bond, and which may be linear or branched orcombinations thereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

The term “alkoxy” means alkyl chains of the designated length whichcontain at least one ether linkage and which may be linear or branchedor combinations thereof. Examples of alkoxy include methoxy, ethoxy,1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, methylmethoxy, methylethoxy,methyl-1-propoxy, methyl-2-propoxy, ethyl-2-methoxy, ethyl-1-methoxy andthe like.

The term “halogen” includes fluorine, chlorine, bromine and iodine.

The term “C₁₋₄ alkyliminoyl” means C₁₋₃C(═NH)—.

The term “aryl” includes mono- or bicyclic aromatic rings containingonly carbon atoms. Examples of aryl include phenyl and naphthyl.

The term “heteroaryl” includes mono- and bicyclic aromatic ringscontaining from 1 to 4 heteroatoms selected from nitrogen, oxygen andsulfur. Examples thereof include, but are not limited to, pyridinyl,furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, triazolyl, triazinyl,tetrazolyl, thiadiazolyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl,isoquinolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl,benzthiazolyl, benzoxazolyl, and the like. In one embodiment of thepresent invention, heteroaryl is selected from the group consisting ofpyridinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, triazolyl,triazinyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxathiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,quinolyl, isoquinolyl, benzimidazolyl, benzofuryl, benzothienyl,indolyl, benzthiazolyl, and benzoxazolyl. Bicyclic heteroaromatic ringsinclude, but are not limited to, benzothiadiazole, indole,benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole,quinoline, quinazoline, benzotriazole, benzoxazole, isoquinoline,purine, furopyridine, thienopyridine, benzisodiazole,triazolopyrimidine, and 5,6,7,8-tetrahydroquinoline.

The term “cycloalkyl” includes mono- or bicyclic non-aromatic ringscontaining only carbon atoms. Examples of cycloalkyl include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl.

The term “heterocycloalkyl” is intended to include non-aromaticheterocycles containing one to four heteroatoms selected from nitrogen,oxygen and sulfur. Examples of heterocycloalkyls include, but are notlimited to, azetidine, piperidine, morpholine, thiamorpholine,pyrrolidine, imidazolidine, tetrahydrofuran, piperazine,1-thia-4-aza-cyclohexane.

The term “5-10 membered aromatic monocyclic or bicyclic heterocyclicring” means a 5- or 6-membered aromatic heterocyclic ring or a fusedbicyclic aromatic ring, which may contain one to three of theheteroatoms selected from nitrogen, oxygen and sulfur, and includes, butis not limited to, furyl, thienyl, isoxazolyl, pyridyl, pyrimidinyl,benzofuranyl, and benzothienyl.

Certain of the above defined terms may occur more than once in the aboveformula and upon such occurrence each term shall be definedindependently of the other; thus for example, NR⁴R⁴ may represent NH₂,NHCH₃, N(CH₃)CH₂CH₃, and the like.

The term “subject” means a mammal. One embodiment of the term “mammal”is a “human,” said human being either male or female. The instantcompounds are also useful for treating or preventing obesity and obesityrelated disorders in cats and dogs. As such, the term “mammal” includescompanion animals such as cats and dogs. The term “mammal in needthereof” refers to a mammal who is in need of treatment or prophylaxisas determined by a researcher, veterinarian, medical doctor or otherclinician.

The term “composition”, as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

By a cholecystokinin receptor “agonist” is meant an endogenous or drugsubstance or compound that can interact with a cholecystokinin receptorand initiate a pharmacological or biochemical response characteristic ofcholecystokinin receptor activation. The “agonistic” properties of thecompounds of the present invention were measured in the functional assaydescribed below.

By “binding affinity” is meant the ability of a compound/drug to bind toits biological target, in the present instance, the ability of acompound of formula I, II and III, to bind to a cholecystokininreceptor. Binding affinities for the compounds of the present inventionwere measured in the binding assay described below and are expressed asIC₅₀'s.

“Efficacy” describes the relative intensity of response which differentagonists produce even when they occupy the same number of receptors andwith the same affinity. Efficacy is the property that describes themagnitude of response. Properties of compounds can be categorized intotwo groups, those which cause them to associate with the receptors(binding affinity) and those that produce a stimulus (efficacy). Theterm “efficacy” is used to characterize the level of maximal responsesinduced by agonists. Not all agonists of a receptor are capable ofinducing identical levels of maximal responses. Maximal response dependson the efficiency of receptor coupling, that is, from the cascade ofevents, which, from the binding of the drug to the receptor, leads tothe desired biological effect.

The functional activities expressed as EC₅₀'s and the “agonist efficacy”for the compounds of the present invention at a particular concentrationwere measured in the functional assay described below. The CCK1R activeand selective agonists of the present invention have an IC₅₀≦500 nM,preferably IC₅₀<100 nM, more preferably IC₅₀<10 nM, and most preferablyIC₅₀<1 nM, while having at least 100-fold and preferably >1000-foldselectivity over CCK2R. The CCK1R active and selective agonists of thepresent invention have an EC₅₀≦500 nM, preferably EC₅₀<100 nM, morepreferably EC₅₀<10 nM, and most preferably EC₅₀<1 nM, while having atleast 100-fold, and preferably >1000-fold selectivity over CCK2R.

Compounds of formula I, II and III, may contain one or more asymmetricor chiral centers and can exist in different stereoisomeric forms, suchas racemates and racemic mixtures, single enantiomers, enantiomericmixtures, individual diastereomers and diastereomeric mixtures. Allstereoisomeric forms of the intermediates and compounds of the presentinvention as well as mixtures thereof, including racemic anddiastereomeric mixtures, which possess properties useful in thetreatment of the conditions discussed herein or are intermediates usefulin the preparation of compounds having such properties, form a part ofthe present invention.

Generally, one of the enantiomers will be more active biologically thanthe other enantiomer. Racemic mixtures can subsequently be separatedinto each enantiomer using standard conditions, such as resolution orchiral chromatography. Diastereomeric mixtures may be separated intotheir individual diastereoisomers on the basis of their physicalchemical differences by methods well known to those skilled in the art,such as by chiral chromatography using an optically active stationaryphase and/or fractional crystallization from a suitable solvent.Absolute stereochemistry may be determined by X-ray crystallography ofcrystalline products or crystalline intermediates which are derivatized,if necessary, with a reagent containing an asymmetric center of knownabsolute configuration. Enantiomers may be separated by use of a chiralHPLC column and by converting the enantiomeric mixture into adiastereomeric mixture by reaction with an appropriate optically activecompound (e.g., chiral auxiliary such as a chiral alcohol or Mosher'sacid chloride), separating the diastereoisomers and converting (e.g.,hydrolyzing) the individual diastereoisomers to the corresponding pureenantiomers. Alternatively, any stereoisomer of a compound of thegeneral formula I, II and III may be obtained by stereospecificsynthesis using optically pure starting materials or reagents of knownabsolute configuration.

The present invention includes all such isomeric forms of the compoundsof formula I, II and III, including the E and Z geometric isomers ofdouble bonds and mixtures thereof. A number of the compounds of thepresent invention and intermediates therefor exhibit tautomerism andtherefore may exist in different tautomeric forms under certainconditions. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. A specificexample of a proton tautomer is an imidazole moiety where the hydrogenmay migrate between the ring nitrogens. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons. Allsuch tautomeric forms (e.g., all keto-enol and imine-enamine forms) arewithin the scope of the invention. The depiction of any particulartautomeric form in any of the structural formulas herein is not intendedto be limiting with respect to that form, but is meant to berepresentative of the entire tautomeric set.

The present invention also encompasses isotopically labeled compoundswhich are identical to the compounds of Formula (I) or intermediatesthereof but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into the intermediates or compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C; 14C,13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I and 36Cl,respectively. Compounds of the present invention, prodrugs thereof andpharmaceutically acceptable salts, hydrates and solvates of saidcompounds and of said prodrugs which contain the aforementioned isotopesand/or other isotopes of other atoms are within the scope of the presentinvention. Certain isotopically labeled compounds of the presentinvention (e.g., those labeled with 3H and 14C) are useful in compoundand/or substrate tissue distribution assays. Tritiated (i.e., 3H) andcarbon-14 (i.e., 14C) isotopes are particularly preferred for their easeof preparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., 2H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as 15O,13N, 11C, and 18F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present invention can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein by substituting an isotopically labeled reagentfor a non-isotopically labeled reagent.

The compounds of the present invention and intermediates may exist inunsolvated as well as solvated forms with solvents such as water,ethanol, isopropanol and the like, and both solvated and unsolvatedforms are included within the scope of the invention. Solvates for usein the methods aspect of the invention should be with pharmaceuticallyacceptable solvents. It will be understood that the compounds of thepresent invention include hydrates, solvates, polymorphs, crystalline,hydrated crystalline and amorphous forms of the compounds of the presentinvention, and pharmaceutically acceptable salts thereof.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, lithium, magnesium, potassium, and sodium salts.Salts derived from pharmaceutically acceptable organic non-toxic basesinclude salts of primary, secondary, and tertiary amines, substitutedamines including naturally occurring substituted amines, cyclic amines,and basic ion exchange resins, such as arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, TEA, trimethylamine, tripropylamine,tromethamine, and the like.

When the compound of formula I, II and III is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric,gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric,pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric,tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like.Particularly preferred are citric, fumaric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids. It will be understoodthat, as used herein, references to the compounds of formula I, II andIII are meant to also include the pharmaceutically acceptable salts,such as the hydrochloride salts and trifluoroacetic acid salts.

Compounds of formula I, II and III are cholecystokinin receptor ligandsand as such are useful in the treatment, control or prevention ofdiseases, disorders or conditions responsive to the modulation of one ormore of the cholecystokinin receptors. In particular, the compounds offormula I, II and III act as cholecystokinin-1 receptor agonists usefulin the treatment, control or prevention of diseases, disorders orconditions responsive to the activation of the cholecystokinin-1receptor. Such diseases, disorders or conditions include, but are notlimited to, obesity (by reducing food intake, reducing appetite,increasing metabolic rate, increasing satiety, reducing carbohydratecraving, reducing gastric emptying), diabetes mellitus (by enhancingglucose tolerance, decreasing insulin resistance), bulimia nervosa andrelated eating disorders, dyslipidemia, hypertension, hyperlipidemia,osteoarthritis, cancer, gall stones, cholelithiasis, cholecystitis, gallbladder disease, sleep apnea, depression, anxiety, compulsion, neuroses,irritable bowel syndrome, inflammatory bowel syndrome, constipation,pain, neuroprotective and cognitive and memory enhancement including thetreatment of Alzheimer's disease. Such diseases, conditions anddisorders also include non-obese overweight conditions and normal weightconditions where weight control or management is desired in order toprevent an obese or overweight condition from developing, or to maintaina healthy weight.

The compounds and compositions of the present invention are useful forthe treatment or prevention of disorders associated with excessive foodintake, such as obesity and obesity-related disorders. The obesityherein may be due to any cause, whether genetic or environmental.

The obesity-related disorders herein are associated with, caused by, orresult from obesity. Examples of obesity-related disorders includeovereating, binge eating, bulimia nervosa, hypertension, type 2diabetes, elevated plasma insulin concentrations, hyperinsulinemia,insulin resistance, glucose intolerance, dyslipidemia, hyperlipidemia,endometrial cancer, breast cancer, prostate cancer, kidney cancer, coloncancer, osteoarthritis, obstructive sleep apnea, cholelithiasis,cholecystitis, gallstones, gout, gallbladder disease, abnormal heartrhythms and arrythmias, myocardial infarction, congestive heart failure,coronary heart disease, angina pectoris, sudden death, stroke, metabolicsyndrome, psychological disorders (depression, eating disorders,distorted bodyweight, and low self esteem), and other pathologicalconditions showing reduced metabolic activity or a decrease in restingenergy expenditure as a percentage of total fat-free mass, e.g, childrenwith acute lymphoblastic leukemia. Further examples of obesity-relateddisorders are sexual and reproductive dysfunction, such as polycysticovary disease, infertility, hypogonadism in males and hirsutism infemales, gastrointestinal motility disorders, such as obesity-relatedgastro-esophageal reflux, respiratory disorders, such asobesity-hypoventilation syndrome (Pickwickian syndrome), cardiovasculardisorders, inflammation, such as systemic inflammation of thevasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia,lower back pain, gallbladder disease, gout, and kidney cancer.Additionally, the present compounds are useful in the treatment of anycondition in which it is desirable to lose weight or to reduce foodintake. Additionally, the present compounds are useful in the treatmentof any condition in which it is desirable to enhance cognition andmemory, such as Alzheimer's Disease. The compositions of the presentinvention are also useful for reducing the risk of secondary outcomes ofobesity, such as reducing the risk of left ventricular hypertrophy.Therefore, the present invention provides methods of treatment orprevention of such diseases, conditions and/or disorders modulated byCCK-1 receptor agonists in an animal which comprises administering tothe animal in need of such treatment a compound of formula I, II or III,in particular a therapeutically or prophylactically effective amountthereof.

Some agonists encompassed by formula I, II and III show highly selectiveaffinity for the cholecystokinin-1 receptor (CCK-1R) relative tocholecystokinin-2 receptor CCK-2R (also known as the CCK-B receptor),which makes them especially useful in the prevention and treatment ofobesity, diabetes, and obesity related disorders. Compounds of thepresent invention are at least 500 fold more selective for the CCK-1receptor than for the CCK-2 receptor.

The term “metabolic syndrome”, also known as syndrome X, is defined inthe Third Report of the National Cholesterol Education Program ExpertPanel on Detection, Evaluation and Treatment of High Blood Cholesterolin Adults (ATP-III). E. S. Ford et al., JAMA, vol. 287 (3), Jan. 16,2002, pp 356-359. Briefly, a person is defined as having metabolicsyndrome if the person has three or more of the following symptoms:abdominal obesity, hypertriglyceridemia, low HDL cholesterol, high bloodpressure, and high fasting plasma glucose. The criteria for these aredefined in ATP-m. The term “diabetes,” as used herein, includes bothinsulin-dependent diabetes mellitus (i.e., IDDM, also known as type Idiabetes) and non-insulin-dependent diabetes mellitus (i.e., NIDDM, alsoknown as Type II diabetes). Type I diabetes, or insulin-dependentdiabetes, is the result of an absolute deficiency of insulin, thehormone which regulates glucose utilization. Type II diabetes, orinsulin-independent diabetes (i.e., non-insulin-dependent diabetesmellitus), often occurs in the face of normal, or even elevated levelsof insulin and appears to be the result of the inability of tissues torespond appropriately to insulin. Most of the Type II diabetics are alsoobese. The compositions of the present invention are useful for treatingboth Type I and Type II diabetes. The compositions are especiallyeffective for treating Type II diabetes. The compounds or combinationsof the present invention are also useful for treating and/or preventinggestational diabetes mellitus.

Treatment of diabetes mellitus refers to the administration of acompound or combination of the present invention to treat diabetes. Oneoutcome of treatment may be decreasing the glucose level in a subjectwith elevated glucose levels. Another outcome of treatment may beimproving glycemic control. Another outcome of treatment may bedecreasing insulin levels in a subject with elevated insulin levels.Another outcome of treatment may be decreasing plasma triglycerides in asubject with elevated plasma triglycerides. Another outcome of treatmentmay be lowering LDL cholesterol in a subject with high LDL cholesterollevels. Another outcome of treatment may be increasing HDL cholesterolin a subject with low HDL cholesterol levels. Another outcome may bedecreasing the LDL/HDL ratio in a subject in need thereof. Anotheroutcome of treatment may be increasing insulin sensitivity. Anotheroutcome of treatment may be enhancing glucose tolerance in a subjectwith glucose intolerance. Another outcome of treatment may be decreasinginsulin resistance in a subject with increased insulin resistance orelevated levels of insulin. Another outcome may be decreasingtriglycerides in a subject with elevated triglycerides. Yet anotheroutcome may be improving LDL cholesterol, non-HDL cholesterol,triglyceride, HDL cholesterol or other lipid analyte profiles.Prevention of diabetes mellitus refers to the administration of acompound or combination of the present invention to prevent the onset ofdiabetes in a subject at risk thereof.

“Obesity” is a condition in which there is an excess of body fat. Theoperational definition of obesity is based on the Body Mass Index (BMI),which is calculated as body weight per height in meters squared (kg/m²).“Obesity” refers to a condition whereby an otherwise healthy subject hasa Body Mass Index (BMI) greater than or equal to 30 kg/m², or acondition whereby a subject with at least one co-morbidity has a BMIgreater than or equal to 27 kg/m². An “obese subject” is an otherwisehealthy subject with a Body Mass Index (BMI) greater than or equal to 30kg/m² or a subject with at least one co-morbidity with a BMI greaterthan or equal to 27 kg/m². A “subject at risk of obesity” is anotherwise healthy subject with a BMI of 25 kg/m² to less than 30 kg/m²or a subject with at least one co-morbidity with a BMI of 25 kg/m² toless than 27 kg/m². The increased risks associated with obesity occur ata lower Body Mass Index (BMI) in Asians. In Asian countries, includingJapan, “obesity” refers to a condition whereby a subject with at leastone obesity-induced or obesity-related co-morbidity, that requiresweight reduction or that would be improved by weight reduction, has aBMI greater than or equal to 25 kg/m². In Asian countries, includingJapan, an “obese subject” refers to a subject with at least oneobesity-induced or obesity-related co-morbidity that requires weightreduction or that would be improved by weight reduction, with a BMIgreater than or equal to 25 kg/m². In Asia-Pacific, a “subject at riskof obesity” is a subject with a BMI of greater than 23 kg/m² to lessthan 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes, non-insulin dependent diabetes mellitus-type II(2), impaired glucose tolerance, impaired fasting glucose, insulinresistance syndrome, dyslipidemia, hypertension, hyperuricacidemia,gout, coronary artery disease, myocardial infarction, angina pectoris,sleep apnea syndrome, Pickwickian syndrome, fatty liver; cerebralinfarction, cerebral thrombosis, transient ischemic attack, orthopedicdisorders, arthritis deformans, lumbodynia, emmeniopathy, andinfertility. In particular, co-morbidities include: hypertension,hyperlipidemia, dyslipidemia, glucose intolerance, cardiovasculardisease, sleep apnea, diabetes mellitus, and other obesity-relatedconditions.

Treatment of obesity and obesity-related disorders refers to theadministration of the compounds or combinations of the present inventionto reduce or maintain the body weight of an obese subject. One outcomeof treatment may be reducing the body weight of an obese subjectrelative to that subject's body weight immediately before theadministration of the compounds or combinations of the presentinvention. Another outcome of treatment may be preventing body weightregain of body weight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of treatment may be decreasing theoccurrence of and/or the severity of obesity-related diseases. Thetreatment may suitably result in a reduction in food or calorie intakeby the subject, including a reduction in total food intake, or areduction of intake of specific components of the diet such ascarbohydrates or fats; and/or the inhibition of nutrient absorption;and/or the inhibition of the reduction of metabolic rate; and in weightreduction in subjects in need thereof. The treatment may also result inan alteration of metabolic rate, such as an increase in metabolic rate,rather than or in addition to an inhibition of the reduction ofmetabolic rate; and/or in minimization of the metabolic resistance thatnormally results from weight loss. Prevention of obesity andobesity-related disorders refers to the administration of the compoundsor combinations of the present invention to reduce or maintain the bodyweight of a subject at risk of obesity. One outcome of prevention may bereducing the body weight of a subject at risk of obesity relative tothat subject's body weight immediately before the administration of thecompounds or combinations of the present invention. Another outcome ofprevention may be preventing body weight regain of body weightpreviously lost as a result of diet, exercise, or pharmacotherapy.Another outcome of prevention may be preventing obesity from occurringif the treatment is administered prior to the onset of obesity in asubject at risk of obesity. Another outcome of prevention may bedecreasing the occurrence and/or severity of obesity-related disordersif the treatment is administered prior to the onset of obesity in asubject at risk of obesity. Moreover, if treatment is commenced inalready obese subjects, such treatment may prevent the occurrence,progression or severity of obesity-related disorders, such as, but notlimited to, arteriosclerosis, Type II diabetes, polycystic ovarydisease, cardiovascular diseases, osteoarthritis, hypertension,dyslipidemia, insulin resistance, hypercholesterolemia,hypertriglyceridemia, and cholelithiasis.

The terms “administration of” and or “administering” a compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to a subject in need of treatment. Theadministration of the compounds of the present invention in order topractice the present methods of therapy is carried out by administeringa therapeutically effective amount of the compound to a subject in needof such treatment or prophylaxis. The need for a prophylacticadministration according to the methods of the present invention isdetermined via the use of well known risk factors.

The term “therapeutically effective amount” as used herein means theamount of the active compound that will elicit the biological or medicalresponse in a tissue, system, subject, mammal, or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disorderbeing treated. The novel methods of treatment of this invention are fordisorders known to those skilled in the art. The term “prophylacticallyeffective amount” as used herein means the amount of the active compoundthat will elicit the biological or medical response in a tissue, system,subject, mammal, or human that is being sought by the researcher,veterinarian, medical doctor or other clinician, to prevent the onset ofthe disorder in subjects as risk for obesity or the disorder. Thetherapeutically or prophylactically effective amount, or dosage, of anindividual compound is determined, in the final analysis, by thephysician in charge of the case, but depends on factors such as theexact disease to be treated, the severity of the disease and otherdiseases or conditions from which the patient suffers, the chosen routeof administration, other drugs and treatments which the patient mayconcomitantly require, and other factors in the physician's judgement.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing asubject or mammal, especially a human with an effective dosage of acompound of the present invention. For example, oral, rectal, topical,parenteral, ocular, pulmonary, nasal, and the like may be employed.Dosage forms include tablets, troches, dispersions, suspensions,solutions, capsules, creams, ointments, aerosols, and the like.Preferably the compound of Formula I, II or III is administered orallyor topically.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating obesity, in conjunction with diabetes and/orhyperglycemia, or alone, generally satisfactory results are obtainedwhen the compound of formula I, II or III is administered at a dailydosage of from about 0.001 milligram to about 50 milligrams per kilogramof animal body weight, preferably given in a single dose or in divideddoses two to six times a day, or in sustained release form. In the caseof a 70 kg adult human, the total daily dose will generally be fromabout 0.07 milligrams to about 3500 milligrams. This dosage regimen maybe adjusted to provide the optimal therapeutic response. When treatingdiabetes mellitus and/or hyperglycemia, as well as other diseases ordisorders for which the compound of formula I, II or III is useful,generally satisfactory results are obtained when the compounds of thepresent invention are administered at a daily dosage of from about 0.001milligram to about 50 milligram per kilogram of animal body weight,preferably given in a single dose or in divided doses two to six times aday, or in sustained release form. In the case of a 70 kg adult human,the total daily dose will generally be from about 0.07 milligrams toabout 3500 milligrams. This dosage regimen may be adjusted to providethe optimal therapeutic response. When treating dyslipidemia, bulimianervosa, and gallstones satisfactory results are obtained when thecompound of formula I, II or III is administered at a daily dosage offrom about 0.001 milligram to about 50 milligrams per kilogram of animalbody weight, preferably given in a single dose or in divided doses twoto six times a day, or in sustained release form. In the case of a 70 kgadult human, the total daily dose will generally be from about 0.07milligrams to about 3500 milligrams. This dosage regimen may be adjustedto provide the optimal therapeutic response.

In the case where an oral composition is employed, a suitable dosagerange is, e.g. from about 0.01 mg to about 1500 mg of a compound ofFormula I, II or III per day, preferably from about 0.1 mg to about 600mg per day, more preferably from about 0.1 mg to about 100 mg per day.For oral administration, the compositions are preferably provided in theform of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05,0.1, 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30, 40, 50, 100, 250, 500, 600,750, 1000, 1250 or 1500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Foruse where a composition for intranasal administration is employed,intranasal formulations for intranasal administration comprising0.001-10% by weight solutions or suspensions of the compound of formulaI, II or III in an acceptable intranasal formulation may be used. Foruse where a composition for intravenous administration is employed, asuitable dosage range is from about 0.001 mg to about 50 mg, preferablyfrom 0.01 mg to about 50 mg, more preferably 0.1 mg to 10 mg, of acompound of formula I, II or III per kg of body weight per day. Thisdosage regimen may be adjusted to provide the optimal therapeuticresponse. It may be necessary to use dosages outside these limits insome cases. For the treatment of diseases of the eye, ophthalmicpreparations for ocular administration comprising 0.001-1% by weightsolutions or suspensions of the compound of formula I, II or III in anacceptable ophthalmic formulation may be used.

The magnitude of prophylactic or therapeutic dosage of the compounds ofthe present invention will, of course, vary depending on the particularcompound employed, the mode of administration, the condition beingtreated and the severity of the condition being treated. It will alsovary according to the age, weight and response of the individualpatient. Such dosage may be ascertained readily by a person skilled inthe art.

A Compound of formula I, II or III may be used in combination with otherdrugs that are used in the treatment/prevention/suppression oramelioration of the diseases or conditions for which compounds offormula I, II and III are useful. Such other drugs may be administered,by a route and in an amount commonly used therefor, contemporaneously orsequentially with a compound of formula I, II or III. When a compound offormula I, II or III is used contemporaneously with one or more otherdrugs, a pharmaceutical composition containing such other drugs inaddition to the compound of Formula I is preferred. Accordingly, thepharmaceutical compositions of the present invention include those thatalso contain one or more other active ingredients, in addition to acompound of formula I, II or III.

Examples of other active ingredients that may be combined with acompound of formula I, II and III for the treatment or prevention ofobesity and/or diabetes, either administered separately or in the samepharmaceutical compositions, include, but are not limited to:

(a) insulin sensitizers including (i) PPARγ antagonists such asglitazones (e.g. ciglitazone; darglitazone; englitazone; isaglitazone(MCC-555); pioglitazone; rosiglitazone; troglitazone; tularik; BRL49653;CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512, and the like), andcompounds disclosed in WO 97/10813, WO 97/27857, WO 97/28115, WO97/28137, and WO 97/27847; (iii) biguanides such as metformin andphenformin;

(b) insulin or insulin mimetics, such as biota, LP-100, novarapid,insulin detemir, insulin lispro, insulin glargine, insulin zincsuspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH₂);

(c) sulfonylureas, such as acetohexamide; chlorpropamide; diabinese;glibenclamide; glipizide; glyburide; glimepiride; gliclazide;glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide;

(d) α-glucosidase inhibitors, such as acarbose, adiposine; camiglibose;emiglitate; miglitol; voglibose; pradimicin-Q; salbostatin; trestatin,tendamistate, CKD-711; MDL-25,637; MDL-73,945; and MOR 14, and the like;

(e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin,rivastatin, rosuvastatin, simvastatin, and other statins), (ii) bileacid absorbers/sequestrants, such as cholestyramine, colestipol,dialkylaminoalkyl derivatives of a cross-linked dextran; Colestid®;LoCholest®, and the like, (ii) nicotinyl alcohol, nicotinic acid or asalt thereof, (iii) proliferator-activater receptor α agonists such asfenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate andbenzafibrate), (iv) inhibitors of cholesterol absorption such as stanolesters, beta-sitosterol, sterol glycosides such as tiqueside; andazetidinones such as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics;

(f) PPARα agonists such as beclofibrate, benzafibrate, ciprofibrate,clofibrate, etofibrate, fenofibrate, and gemfibrozil; and other fibricacid derivatives, such as Atromid®, Lopid® and Tricor®, and the like,and PPARα agonists as described in WO 97/36579 by Glaxo;

(g) PPARδ agonists, such as those disclosed in WO97/28149;

(h) PPAR α/δ agonists, such as muraglitazar, and the compounds disclosedin U.S. Pat. No. 6,414,002;

(i) smoking cessation agents, such as a nicotine agonist or a partialnicotine agonist such as varenicline, or a monoamine oxidase inhibitor(MAOI), or another active ingredient demonstrating efficacy in aidingcessation of tobacco consumption; for example, an antidepressant such asbupropion, doxepine, ornortriptyline; or an anxiolytic such as buspironeor clonidine; and

(j) anti-obesity agents, such as (1) growth hormone secretagogues,growth hormone secretagogue receptor agonists/antagonists, such asNN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429, andL-163,255, and such as those disclosed in U.S. Pat. Nos. 5,536,716, and6,358,951, U.S. Patent Application Nos. 2002/049196 and 2002/022637, andPCT Application Nos. WO 01/56592 and WO 02/32888; (2) protein tyrosinephosphatase-1B (PTP-1B) inhibitors; (3) cannabinoid receptor ligands,such as cannabinoid CB1 receptor antagonists or inverse agonists, suchas rimonabant (Sanofi Synthelabo), AMT-251, and SR-14778 and SR 141716A(Sanofi Synthelabo), SLV-319 (Solvay), BAY 65-2520 (Bayer), and thosedisclosed in U.S. Pat. Nos. 5,532,237, 4,973,587, 5,013,837, 5,081,122,5,112,820, 5,292,736, 5,624,941, 6,028,084, PCT Application Nos. WO96/33159, WO 98/33765, WO98/43636, WO98/43635, WO 01/09120, WO98/31227,WO98/41519, WO98/37061, WO00/10967, WO00/10968, WO97/29079, WO99/02499,WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO03/007887, WO 04/048317, and WO 05/000809; and EPO Application No.EP-658546, EP-656354, EP-576357; (4) anti-obesity serotonergic agents,such as fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5)β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda),CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A, and such asthose disclosed in U.S. Pat. No. 5,705,515, and U.S. Pat. No. 5,451,677and PCT Patent Publications WO94/18161, WO95/29159, WO97/46556,WO98/04526 and WO98/32753, WO 01/74782, and WO 02/32897; (6) pancreaticlipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267,lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferylphosphate, and those disclosed in PCT Application No. WO 01/77094; (7)neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIB30 3304,LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8)neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X,GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A,CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, andthose disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354;6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332;6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and6,723,847, hereby incorporated by reference in their entirety; EuropeanPatent Nos. EP-01010691, and EP-01044970; and PCT International PatentPublication Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO97/20823, WO 98/24768; WO 98/25907; WO 98/25908; WO 98/27063, WO98/47505; WO 98/40356; WO 99/15516; WO 99/27965; WO 00/64880, WO00/68197, WO 00/69849, WO 01/09120, WO 01/14376; WO 01/85714, WO01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO02/22592, WO 0248152, and WO 02/49648; WO 02/094825; WO 03/014083; WO03/10191; WO 03/092889; WO 04/002986; and WO 04/031175; (9)melanin-concentrating hormone (MCH) receptor antagonists, such as thosedisclosed in WO 01/21577 and WO 01/21169; (10) melanin-concentratinghormone 1 receptor (MCH1R) antagonists, such as T-226296 (Takeda), andthose disclosed in PCT Patent Application Nos. WO 01/82925, WO 01/87834,WO 02/051809, WO 02/06245, WO 02/076929, WO 02/076947, WO 02/04433, WO02/51809, WO 02/083134, WO 02/094799, WO 03/004027, and Japanese PatentApplication Nos. JP 13226269, and JP 2004-139909; (11)melanin-concentrating hormone 2 receptor (MCH2R) agonist/antagonists;(12) orexin-1 receptor antagonists, such as SB-334867-A, and thosedisclosed in PCT Patent Application Nos. WO 01/96302, WO 01/68609, WO02/51232, and WO 02/51838; (13) serotonin reuptake inhibitors such asfluoxetine, paroxetine, and sertraline, and those disclosed in U.S. Pat.No. 6,365,633, and PCT Patent Application Nos. WO 01/27060 and WO01/162341; (14) melanocortin agonists, such as Melanotan II, CHIR86036(Chiron), ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141,and PT-14 (Palatin); (15) other MC4R (melanocortin 4 receptor) agonists,such as those disclosed in: U.S. Pat. Nos. 6,410,548; 6,294,534;6,350,760; 6,458,790; 6,472,398; 6,376,509; and 6,818,658; US PatentPublication No. US2002/0137664; US2003/0236262; US2004/009751;US2004/0092501; and PCT Application Nos. WO 99/64002; WO 00/74679; WO01/70708; WO 01/70337; WO 01/74844; WO 01/91752; WO 01/991752; WO02/15909; WO 02/059095; WO 02/059107; WO 02/059108; WO 02/059117; WO02/067869; WO 02/068387; WO 02/068388; WO 02/067869; WO 02/11715; WO02/12166; WO 02/12178; WO 03/007949; WO 03/009847; WO 04/024720; WO04/078716; WO 04/078717; WO 04/087159; WO 04/089307; and WO 05/009950;(16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C) agonists, suchas BVT933, DPCA37215, WAY161503, R-1065, and those disclosed in U.S.Pat. No. 3,914,250, and PCT Application Nos. WO 02/36596, WO 02/48124,WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456, and WO02/40457; (18) galanin antagonists; (19) CCK agonists; (20) other CCK-1(cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180,A-71378, A-71623 and SR146131, and those described in U.S. Pat. No.5,739,106; (21) GLP-1 agonists; (22) corticotropin-releasing hormoneagonists; (23) histamine receptor-3 (H3) modulators; (24) histaminereceptor-3 (H3) antagonists/inverse agonists, such as hioperamide,3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate, clobenpropit,iodophenpropit, imoproxifan, GT2394 (Gliatech), and those described anddisclosed in PCT Application No. WO 02/15905, andO-[3-(1H-imidazol-4-yl)propanol]-carbamates (Kiec-Kononowicz, K. et al.,Pharmazie, 55:349-55 (2000)), piperidine-containing histamineH3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32(2001), benzophenone derivatives and related compounds (Sasse, A. etal., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substitutedN-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)),and proxifan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43(2000)); (25) β-hydroxy steroid dehydrogenase-1 inhibitors (β-HSD-1);26) PDE (phosphodiesterase) inhibitors, such as theophylline,pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide,rolipram, and cilomilast; (27) phosphodiesterase-3B (PDE3B) inhibitors;(28) NE (norepinephrine) transport inhibitors, such as GW 320659,despiramine, talsupram, and nomifensine; (29) ghrelin receptorantagonists, such as those disclosed in PCT Application Nos. WO01/87335, and WO 02/08250; (30) leptin, including recombinant humanleptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin(Amgen); (31) leptin derivatives, such as those disclosed in U.S. Pat.Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283, and PCT InternationalPublication Nos. WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO96/23517, WO 96/23518, WO 96/23519, and WO 96/23520; (32) BRS3 (bombesinreceptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-1 81771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD 170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron), and those disclosed in PCTApplication Nos. WO 94/09134, WO 98/22128, and WO 99/43813; (35)monoamine reuptake inhibitors, such as sibutramine, and those disclosedin U.S. Pat. Nos. 4,746,680, 4,806,570, and 5,436,272, U.S. PatentPublication No. 2002/0006964 and PCT Application Nos. WO 01/27068, andWO 01/62341; (36) UCP-1 (uncoupling protein-1), 2, or 3 activators, suchas phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid, and those disclosed in PCT PatentApplication No. WO 99/00123; (37) thyroid hormone

agonists, such as KB-2611 (KaroBioBMS), and those disclosed in PCTApplication No. WO 02/15845, and Japanese Patent Application No. JP2000256190; (38) FAS (fatty acid synthase) inhibitors, such as Ceruleninand C75; (39) DGAT1 (diacylglycerol acyltransferase 1) inhibitors; (40)DGAT2 (diacylglycerol acyltransferase 2) inhibitors; (41) ACC2(acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoid antagonists;(43) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa,M. et al., Obesity Research, 9:202-9 (2001); (44) dipeptidyl peptidaseIV (DP-IV) inhibitors, such as isoleucine thiazolidide, valinepyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225, TMC-2A/2B/2C, FE999011, P9310/K364, VIP 0177, SDZ 274-444 and sitagliptin; and thecompounds disclosed in U.S. Pat. No. 6,699,871, which is incorporatedherein by reference; and International Patent Application Nos. WO03/004498; WO 03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO03/000250; WO 03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO03/000180; and WO 03/000181; (46) dicarboxylate transporter inhibitors;(47) glucose transporter inhibitors; (48) phosphate transporterinhibitors; (49) Metformin (Glucophage®); and (50) Topiramate(Topimax®); and (50) peptide YY, PYY 3-36, peptide YY analogs,derivatives, and fragments such as BIM-43073D, BIM-43004C (Olitvak, D.A. et al., Dig. Dis. Sci. 44(3):643-48 (1999)), and those disclosed inU.S. Pat. No. 5,026,685, U.S. Pat. No. 5,604,203, U.S. Pat. No.5,574,010, U.S. Pat. No. 5,696,093, U.S. Pat. No. 5,936,092, U.S. Pat.No. 6,046,162, U.S. Pat. No. 6,046,167, U.S. Pat. No. 6,093,692, U.S.Pat. No. 6,225,445, U.S. Pat. No. 5,604,203, U.S. Pat. No. 4,002,531,U.S. Pat. No. 4,179,337, U.S. Pat. No. 5,122,614, U.S. Pat. No.5,349,052, U.S. Pat. No. 5,552,520, U.S. Pat. No. 6,127,355, WO95/06058, WO 98/32466, WO 03/026591, WO 03/057235, WO 03/027637, and WO2004/066966, which are incorporated herein by reference; (51)Neuropeptide Y2 (NPY2) receptor agonists such NPY3-36, N acetyl[Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP) as described in Batterham etal., J. Clin. Endocrinol. Metab. 88:3989-3992 (2003), and other Y4agonists such as 1229U91; (54) cyclo-oxygenase-2 inhibitors such asetoricoxib, celecoxib, valdecoxib, parecoxib, lumiracoxib, BMS347070,tiracoxib or JTE522, ABT963, CS502 and GW406381, and pharmaceuticallyacceptable salts thereof; (55) Neuropeptide Y1 (NPY1) antagonists suchas BI3P3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A andthose disclosed in U.S. Pat. No. 6,001,836; and PCT Application Nos. WO96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO01/85173, and WO 01/89528; (56) Opioid antagonists such as nalmefene(Revex®), 3-methoxynaltrexone, naloxone, naltrexone, and those disclosedin: PCT Application No. WO 00/21509; (57) 11p HSD-1 (11-beta hydroxysteroid dehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, andthose disclosed in WO 01/90091, WO 01/90090, WO 01/90092, and U.S. Pat.No. 6,730,690 and US Publication No. US 2004-0133011, which areincorporated by reference herein in their entirety; and (58) aminorex;(59) amphechloral; (60) amphetamine; (61) benzphetamine; (62)chlorphentermine; (63) clobenzorex; (64) cloforex; (65) clominorex; (66)clortermine; (67) cyclexedrine; (68) dextroamphetamine; (69)diphemethoxidine, (70) N-ethylamphetamine; (71) fenbutrazate; (72)fenisorex; (73) fenproporex; (74) fludorex; (75) fluminorex; (76)furfurylmethylamphetamine; (77) levamfetamine; (78) levophacetoperane;(79) mefenorex; (80) metamfepramone; (81) methamphetamine; (82)norpseudoephedrine; (83) pentorex; (84) phendimetrazine; (85)phenmetrazine; (86) picilorex; (87) phytopharm 57; (88) zonisamide, (89)neuromedin U and analogs or derivatives thereof, (90) oxyntomodulin andanalogs or derivatives thereof; (91) Neurokinin-1 receptor antagonists(NK-1 antagonists) such as the compounds disclosed in: U.S. Pat. Nos.5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270,5,494,926, 5,496,833, and 5,637,699; PCT International PatentPublication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688,92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677,92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170,93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064,93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461,94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843,94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639,94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735,94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886,95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382,95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798,95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193,96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197,96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385,96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362,97/18206, 97/19084, 97/19942, 97/21702, and 97/49710; and (92) Qnexa.

Specific compounds of use in combination with a compound of the presentinvention include: simvastatin, mevastatin, ezetimibe, atorvastatin,sitagliptin, metformin, sibutramine, orlistat, Qnexa, topiramate,naltrexone, bupriopion, phentermine, and losartan, losartan withhydrochlorothiazide. Specific CB1 antagonists/inverse agonists of use incombination with a compound of the present invention include: thosedescribed in WO03/077847, including:N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide,N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,and pharmaceutically acceptable salts thereof; as well as those inWO05/000809, which includes the following:3-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-3-(3,5-difluorophenyl)-2,2-dimethylpropanenitrile,1-{1-[1-(4-chlorophenyl)pentyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol,3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((4-chlorophenyl){3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((1S)-1-{1-[(S)-(3-cyanophenyl)(4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,and 5-((4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)thiophene-3-carbonitrile,and pharmaceutically acceptable salts thereof; as well as:3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-chlorophenyl)methyl]benzonitrile,3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-cyanophenyl)methyl]benzonitrile,3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,2,4-oxadiazol-3-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]-methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1H-tetrazole,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1-methyl-1H-tetrazole,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-2-methyl-2H-tetrazole,3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,5-{3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]phenyl}-1,3,4-oxadiazol-2(3H)-one,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-chlorophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,4-{(S)-{3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}-benzonitrile,and pharmaceutically acceptable salts thereof.

Specific NPY5 antagonists of use in combination with a compound of thepresent

invention include:3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,and pharmaceutically acceptable salts and esters thereof.

Specific ACC-1/2 inhibitors of use in combination with a compound of thepresent invention include:1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;(5-{1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}-2H-tetrazol-2-yl)methylpivalate;5-{1′-[(8-cyclopropyl-4-methoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinicacid;1′-(8-methoxy-4-morpholin-4-yl-2-naphthoyl)-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and1′-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and pharmaceutically acceptable salts and esters thereof. Specific MCH1Rantagonist compounds of use in combination with a compound of thepresent invention include:1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one,4-[(4-fluorobenzyl)oxy]-1-{4-[(1-isopropylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,1-[4-(azetidin-3-yloxy)phenyl]-4-[(1-chloropyridin-2-yl)methoxy]pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-propylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,and4-[(5-chloropyridin-2-yl)methoxy]-1-(4-{[(2S)-1-ethylazetidin-2-yl]methoxy}phenyl)pyridin-2(1H)-one,or a pharmaceutically acceptable salt thereof.

Specific DP-IV inhibitors of use in combination with a compound of thepresent invention are selected from7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine.In particular, the compound of formula I is favorably combined with7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine,and pharmaceutically acceptable salts thereof.

Specific H3 (histamine H3) antagonists/inverse agonists of use incombination with a compound of the present invention include: thosedescribed in WO05/077905, including:3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,and pharmaceutically acceptable salts thereof.

Specific CCK1R agonists of use in combination with a compound of thepresent invention include:3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; and3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; and pharmaceutically acceptable salts thereof. Specific MC4Ragonists of use in combination with a compound of the present inventioninclude: 1)(5S)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];2)(5R)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)-piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];3)2-(1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl)-2-methylpropanenitrile;4)1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];5)N-[(3R,4R)-3-({3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-1′H,5H-spiro[furo-[3,4-b]pyridine-7,4′-piperidin]-1′-yl}carbonyl)-4-(2,4-difluorophenyl)-cyclopentyl]-N-methyltetrahydro-2H-pyran-4-amine;6)2-[3-chloro-1′-({(1R,2R)-2-(2,4-difluorophenyl)-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]-cyclopentyl}-carbonyl)-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl]-2-methyl-propane-nitrile;and pharmaceutically acceptable salts thereof. Still further,neurokinin-1 (NK-1) receptor antagonists may be favorably employed incombination with a compound of the present invention. NK-1 receptorantagonists of use in the present invention are fully described in theart. Specific neurokinin-1 receptor antagonists of use in the presentinvention include:(±)-(2R3R,2S3S)—N-{[2-cyclopropoxy-5-(trifluoromethoxy)-phenyl]methyl}-2-phenylpiperidin-3-amine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;aperpitant; CJ17493; GW597599; GW679769; R673; RO67319; R1124; R1204;SSR146977; SSR240600; T-2328; and T2763; or a pharmaceuticallyacceptable salts thereof.

Examples of other anti-obesity agents that can be employed incombination with a compound of formula I, II and III are disclosed in“Patent focus on new anti-obesity agents,” Exp. Opin. Ther. Patents, 10:819-831 (2000); “Novel anti-obesity drugs,” Exp. Opin. Invest. Drugs, 9:1317-1326 (2000); and “Recent advances in feeding suppressing agents:potential therapeutic strategy for the treatment of obesity, Exp. Opin.Ther. Patents, 11: 1677-1692 (2001). The role of neuropeptide Y inobesity is discussed in Exp. Opin. Invest. Drugs, 9:1327-1346 (2000).Cannabinoid receptor ligands are discussed in Exp. Opin. Invest. Drugs,9: 1553-1571 (2000).

The instant invention also includes administration of a singlepharmaceutical dosage formulation which contains both the CCK-1R ligandor agonist in combination with a second active ingredient, as well asadministration of each active agent in its own separate pharmaceuticaldosage formulation. Where separate dosage formulations are used, theindividual components of the composition can be administered atessentially the same time, i.e., concurrently, or at separatelystaggered times, i.e. sequentially prior to or subsequent to theadministration of the other component of the composition. The instantinvention is therefore to be understood to include all such regimes ofsimultaneous or alternating treatment, and the terms “administration”and “administering” are to be interpreted accordingly. Administration inthese various ways are suitable for the present compositions as long asthe beneficial pharmaceutical effect of the combination of the CCK-1Rligand or agonist and the second active ingredient is realized by thepatient at substantially the same time. Such beneficial effect ispreferably achieved when the target blood level concentrations of eachactive ingredient are maintained at substantially the same time. It ispreferred that the combination of the CCK-1R ligand or agonist and thesecond active ingredient be co-administered concurrently on a once-a-daydosing schedule; however, varying dosing schedules, such as the CCK-1Rligand or agonist once a day and the second active ingredient once,twice or more times per day or the CCK-1R ligand or agonist three timesa day and the second active ingredient once, twice or more times perday, is also encompassed herein. A single oral dosage formulationcomprised of both a CCK-1R ligand or agonist and a second activeingredient is preferred. A single dosage formulation will provideconvenience for the patient, which is an important considerationespecially for patients with diabetes or obese patients who may be inneed of multiple medications.

The compounds in the combinations of the present invention may beadministered separately, therefore the invention also relates tocombining separate pharmaceutical compositions into a kit form. The kit,according to this invention, comprises two separate pharmaceuticalcompositions: a first unit dosage form comprising a prophylactically ortherapeutically effective amount of the cholecystokinin-1 receptoragonist, or a pharmaceutically acceptable salt or ester thereof, and apharmaceutically acceptable carrier or diluent in a first unit dosageform, and a second unit dosage form comprising a prophylactically ortherapeutically effective amount of the second active ingredient ordrug, or a pharmaceutically acceptable salt or ester thereof, and apharmaceutically acceptable carrier or diluent in a second unit dosageform. In one embodiment, the kit further comprises a container. Suchkits are especially suited for the delivery of solid oral forms such astablets or capsules. Such a kit preferably includes a number of unitdosages. Such kits can include a card having the dosages oriented in theorder of their intended use. An example of such a kit is a “blisterpack”. Blister packs are well known in the packaging industry and arewidely used for packaging pharmaceutical unit dosage forms. If desired,a memory aid can be provided, for example in the form of numbers,letters, or other markings or with a calendar insert, designating thedays or time in the treatment schedule in which the dosages can beadministered.

Another aspect of the present invention provides pharmaceuticalcompositions which comprise a compound of formula I, II or III, as anactive ingredient or a pharmaceutically acceptable salt thereof, and mayalso contain a pharmaceutically acceptable carrier and optionally othertherapeutic ingredients. The term “pharmaceutically acceptable salts”refers to salts prepared from pharmaceutically acceptable non-toxicbases or acids including inorganic bases or acids and organic bases oracids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In practical use, the compound of formula I, II or III can be combinedas the active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe typical oral dosage unit form, in which case solid pharmaceuticalcarriers are typically employed. If desired, tablets may be coated bystandard aqueous or nonaqueous techniques. Such compositions andpreparations should contain at least 0.1 percent of active compound. Thepercentage of active compound in these compositions may, of course, bevaried and may conveniently be between about 2 percent to about 60percent of the weight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that an effective dosagewill be obtained. The active compounds can also be administeredintranasally as, for example, liquid drops or spray. The tablets, pills,capsules, and the like may also contain a binder such as gum tragacanth,acacia, corn starch or gelatin; excipients such as dicalcium phosphate;a disintegrating agent such as corn starch, potato starch, alginic acid;a lubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin. When a dosage unit form is a capsule, itmay contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Various other materials may be present ascoatings or to modify the physical form of the dosage unit. Forinstance, tablets may be coated with shellac, sugar or both. A syrup orelixir may contain, in addition to the active ingredient, sucrose as asweetening agent, methyl and propylparabens as preservatives, a dye anda flavoring such as cherry or orange flavor.

The Compound of formula I, II or III may also be administeredparenterally. Solutions or suspensions of these active compounds can beprepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds of formula I, II and III of the present invention can beprepared according to the procedures of the following Schemes andExamples, using appropriate materials and are further exemplified by thefollowing specific examples. Moreover, by utilizing the proceduresdescribed herein, one of ordinary skill in the art can readily prepareadditional compounds of the present invention claimed herein. Thecompounds illustrated in the examples are not, however, to be construedas forming the only genus that is considered as the invention. TheExamples further illustrate details for the preparation of the compoundsof the present invention. Those skilled in the art will readilyunderstand that known variations of the conditions and processes of thefollowing preparative procedures can be used to prepare these compounds.The instant compounds are generally isolated in the form of theirpharmaceutically acceptable salts, such as those described previouslyhereinabove. The free amine bases corresponding to the isolated saltscan be generated by neutralization with a suitable base, such as aqueoussodium hydrogencarbonate, sodium carbonate, sodium hydroxide, andpotassium hydroxide, and extraction of the liberated amine free baseinto an organic solvent followed by evaporation. The amine free baseisolated in this manner can be further converted into anotherpharmaceutically acceptable salt by dissolution in an organic solventfollowed by addition of the appropriate acid and subsequent evaporation,precipitation, or crystallization. All temperatures are degrees Celsiusunless otherwise noted. Mass spectra (MS) were measured byelectron-spray ion-mass spectroscopy.

The phrase “standard peptide coupling reaction conditions” meanscoupling a carboxylic acid with an amine using an acid activating agentsuch as EDC, DCC, and BOP in an inert solvent such as dichloromethane inthe presence of a catalyst such as HOBT. The use of protecting groupsfor the amine and carboxylic acid functionalities to facilitate thedesired reaction and minimize undesired reactions is well documented.Conditions required to remove protecting groups are found in standardtextbooks such as Greene, T, and Wuts, P. G. M., Protective Groups inOrganic Synthesis, John Wiley & Sons, Inc., New York, N.Y., 1991. CBZand BOC are commonly used protecting groups in organic synthesis, andtheir removal conditions are known to those skilled in the art. Forexample, CBZ may be removed by catalytic hydrogenation in the presenceof a noble metal or its oxide such as palladium on activated carbon in aprotic solvent such as methanol or ethanol. In cases where catalytichydrogenation is contraindicated due to the presence of otherpotentially reactive functionalities, removal of CBZ groups can also beachieved by treatment with a solution of hydrogen bromide in acetic acidor by treatment with a mixture of TFA and dimethylsulfide. Removal ofBOC protecting groups is carried out with a strong acid, such astrifluoroacetic acid, hydrochloric acid, or hydrogen chloride gas, in asolvent such as methylene chloride, methanol, or ethyl acetate.

Abbreviations Used in the Description of the Preparation of theCompounds of the Present Invention: Ac is acetyl, BOC (Boc) ist-butyloxycarbonyl, BOP isbenzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate,Bn is benzyl, Bu is butyl, calc. or calc'd is Calculated, celite isCelite™ diatomaceous earth, CBZ (Cbz) is benzyloxycarbonyl, c-hex iscyclohexyl, c-pen is cyclopentyl, c-pro is cyclopropyl, DCC isdicyclohexylcarbodiimide, DEAD is diethyl azodicarboxylate, DIEA isdiisopropyl-ethylamine, DMAP is 4-dimethylaminopyridine, DMF isN,N-dimethylformamide, dppf is 1,1′-bis(diphenylphosphino)ferrocene, EDCis 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, eq is equivalent(s),ES-MS and ESI-MS are electron spray ion-mass spectroscopy, Et is ethyl,EtOAc is ethyl acetate, g is gram(s), h or hr is hour(s), HATU isO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, HMPA is hexamethyl phosphoramide, HOAc is aceticacid, HOAT is 1-hydroxy-7-azabenzotriazole, HOBt or HOBT is1-hydroxybenzotriazole, HPLC is high performance liquid chromatography,LC/MS or LC-MASS is liquid chromatography mass spectrum, LDA is lithiumdiisopropylamide, CCK-xR is cholecystokinin receptor (x being a number),L is liter, Me is methyl, MeOH is methanol, MF is molecular formula, minis minutes, mg is milligram(s), mL is milliliter, mmol is millimole(s),MPLC is medium pressure liquid chromatography, MS is mass spectrum, Msis methane sulfonyl, MTBE is tert-butyl methyl ether, NaHMDS is sodiumhexamethyl disilazide, NaOtBu is sodium tert-butoxide, NMM isN-Methylmorpholine, NMO is N-Methylmorpholine-N-oxide, OTf istrifluoromethanesulfonyl, Pd₂(dba)₃ is tris(dibenzylideneacetone)dipalladium (0), Ph is phenyl, Phe is phenyl alanine, Pr is propyl, iPris isopropyl, prep. is prepared, PyBOP isbenzotriazol-1-yloxytripyrrolidine-phosphonium hexafluorophosphate,PyBrop is bromo-tris-pyrrolidino-phosphonium hexafluoro-phosphate, r.t.or rt is room temperature, SCF CO₂ S is super critical fluid carbondioxide, TBAF is tetrabutylammonium fluoride, TEA or Et₃N istriethylamine, Tf is triflate or trifluoromethanesulfonate, TFA istrifluoroacetic acid, THF is tetrahydrofuran, TIPS is triisopropylsilyl,TBDS is tert-butyldimethylsilyl, TBDPS is tert-butyldiphenylsilyl, andTLC is thin-layer chromatography.

Reaction Schemes 1-6 illustrate the methods employed in the synthesis ofthe compounds of the present invention of formula I, II and III. Allsubstituents are as defined above unless indicated otherwise. Thesynthesis of the novel compounds of formula I, II and III which are thesubject of this invention may be accomplished by one or more of severalsimilar routes. The compounds of the present invention can be preparedfrom diaryl imidazole carboxamides such as those of formula V and asubstituted piperazine such as VI using standard coupling conditionsfollowed by additional modifications. The preparation of theseintermediates is described in the following Schemes, wherein X, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are defined above.

Intermediates of formula V are known in the literature or may beconveniently prepared by a variety of methods familiar to those skilledin the art. One route described in the literature (J. H. M. Lange, et.al. J. Med. Chem. 2005, 48, 1823 and I. K. Khanna, et. al. J. Med. Chem.1997, 40, 1634) is illustrated in Scheme 1. Intermediates of formula 1and 2, which are either commercially available or known in theliterature, are treated with a base such as potassiumbis(trimethylsilyl)amide to provide the diaryl amidine 3. Heatingamidine 3 with methyl or ethyl bromopyruvate in the presence of a basesuch as sodium bicarbonate in a solvent such as 2-propanol, 1,4-dioxane,or tetrahydrofuran affords imidazole 4. Subsequent hydrolysis of theester with, for example, lithium or sodium hydroxide provides acid V.

Intermediates VI are commercially available, known in the literature, ormay be prepared as illustrated in Scheme 2 from intermediates 5 and 6.Intermediates 5, wherein L is a suitable nitrogen protecting group suchas tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or trityl (Tr),are either commercially available or known in the literature.Intermediates 6, wherein Y is Cl, Br, I, or triflate, are eithercommercially available, known in the literature, or convenientlyprepared by a variety of methods familiar to those skilled in the art.Intermediates 7 may be prepared by heating 5 and 6 together in thepresence of a base such as sodium tert-butoxide, potassium phosphate, orcesium carbonate in a solvent such as toluene, 1,4-dioxane, orN,N-dimethylformamide with catalytic amounts of a palladium source and atrisubstituted phosphine according to procedures outlined in J. P.Wolfe, et. al. J. Org. Chem. 2000, 65, 1144 and J. P. Wolfe, et. al. J.Org. Chem. 2000, 65, 1158. After coupling, the protecting group of 7 isthen removed with, for example, trifluoroacetic acid or methanolichydrogen chloride in the case of Boc to give the desired amineintermediate VIa.

Intermediates VIb are known in the literature or may be prepared asillustrated in Scheme 3 from intermediates 8 and 9. Intermediates 8,wherein SiR3 is any suitable silicon based alcohol 20 protecting groupsuch as triisopropylsilyl, tert-butyldimethylsilyl, ortert-butyldiphenylsilyl, are conveniently prepared from by a variety ofmethods familiar to those skilled in the art from precursor compoundsknown in the literature in K. Duffy, et. al. J. Med. Chem. 2001, 44,3730-3745. Intermediates 9, wherein P is a suitable nitrogen protectinggroup such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), ortrityl (Tr), are either commercially available or known in theliterature. Intermediates 10 may be prepared by initial transmetallationof bromide 8 with, for example, sec-butyllithium or tert-butyllithiumthen coupling the organolithium intermediate with ketone 9 in a solventsuch as 1,4-dioxane, hexane, or tetrahydrofuran. After coupling, thesilicon protecting group of 10 is then removed with, for example,tetrabutylammonium fluoride in a solvent such as tetrahydrofuran toafford 11. Next, intermediate 11 is converted to the correspondingcarboxylic acid 13 in a two step sequence by first oxidation to aldehyde12 using, for example, the Dess-Martin periodinane reagent in a solventsuch as dichloromethane with pyridine. The aldehyde 12 is then oxidizedto acid 13 by treatment with sodium hypochlorite in a solvent such astert-butyl alcohol with sodium dihydrogen phosphate and2-methyl-2-butene added to buffer the solution. After conversion tomethyl ester 13 using, for example, trimethylsilyldiazomethane, thenitrogen protecting group of 13 is then carefully removed with, forexample, trifluoroacetic acid or methanolic hydrogen chloride at orbelow room temperature in the case of Boc to give the desired amineintermediate VIb.

Alternatively, intermediate 15 may be heated with trifluoroacetic acidin dichloromethane to give the nitrogen deprotected alkene intermediate16 as illustrated in Scheme 4. Alkene 16 may then be hydrogenated with,for example, palladium hydroxide in methanol under a hydrogen atmosphereto give intermediate VIc.

Compound I may be prepared as illustrated in Scheme 5 by couplingintermediates V and VI under standard peptide coupling conditions, forexample, using EDC and HOBT, or HATU and HOAT in the presence of a basesuch as DIEA or triethylamine in a solvent such as DMF ordichloromethane for 3 to 48 hours at ambient temperature to providecompound I where X, and R¹ to R¹⁰ are described above. The product ispurified from unwanted side products, if necessary, byrecrystallization, trituration, preparative thin layer chromatography,flash chromatography on silica gel, such as with a Biotage® apparatus,or HPLC. Compounds that are purified by HPLC may be isolated as thecorresponding salt. Purification of intermediates is achieved in thesame manner.

In some cases the product, compound I, or the synthetic intermediatesillustrated in the above schemes may be further modified, for example,by manipulation of the naphthylene R¹⁰ substituents. These manipulationsmay include, but are not limited to, reduction, oxidation, alkylation,arylation, condensation, acylation, and hydrolysis reactions that arecommonly known to those skilled in the art. One such example isillustrated in Scheme 6. Hydrolysis of ester Ia with, for example,lithium or sodium hydroxide provides acid Ib.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts.

The following intermediates and examples are provided to illustrate theinvention and are not to be construed as limiting the scope of theinvention in any manner.

Intermediate 11-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylic Acid

Step A: N-(3-Ethoxyphenyl)-4-methylbenzenecarboxamidine. To a solutionof 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodiumbis(trimethylsilyl)amide in 5.0 mL of tetrahydrofuran at ambienttemperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and theresulting solution was stirred for 20 min. To this reaction mixture wasslowly added a solution of 0.47 g (4.0 mmol) of p-tolunitrile in 2.0 mLof tetrahydrofuran. The resulting mixture was stirred at ambienttemperature for 5 hrs and then poured into brine (25 mL) anddichloromethane (50 mL). The organic layer was separated and the aqueouslayer was extracted with dichloromethane (25 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated invacuo to yield the title compound as yellow solid which was used withoutfurther purification. LC/MS 255.2 (M+1).

Step B: Ethyl1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate. To amixture of 1.1 g (4.0 mmol) of the compound from Step A and 0.80 g (9.5mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL(4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxedovernight. After cooling to room temperature, the solid was filtered offand the filtrate was concentrated in vacuo. Flash chromatography on aBiotage Horizon® system (silica gel, 5 to 40% ethyl acetate in hexanesgradient then 40% ethyl acetate in hexanes) gave the title compound as ayellow oil. LC/MS 351.2 (M+1).

Step C: 1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylicacid. To a solution of 0.75 g (2.1 mmol) of ethyl1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate in 10mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirredat ambient temperature overnight. Next, hydrochloric acid (2.0 M) wasadded to neutralize the reaction mixture. After removal of the organicsolvents in vacuo, dichloromethane (20 mL) was added and the organiclayer was separated. The aqueous layer was extracted withdichloromethane (10 mL), and the combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to yield the titlecompound as a yellow foam. LC/MS 323.3 (M+1).

Intermediate 21-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylicAcid

Step A:N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-methylbenzenecarboxamidine. To asolution of 0.61 g (4.0 mmol) of 1,4-benzodioxan-6-amine in 5 mL oftetrahydrofuran at ambient temperature was added 2.2 mL (4.4 mmol) of2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide and theresulting solution was stirred for 20 min. To this reaction mixture wasslowly added a solution of 0.47 g (4.0 mmol) of p-tolunitrile in 2 mL oftetrahydrofuran. The resulting mixture was stirred at ambienttemperature for 5 hrs and then poured into brine (25 mL) anddichloromethane (50 mL). The organic layer was separated and the aqueouslayer was extracted with 25 mL of dichloromethane (25 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedin vacuo to yield the title compound as brown crystalline solid, whichwas used without further purification. LC/MS 269.2 (M+1).

Step B: Ethyl1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylate.To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodiumbicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) ofethyl bromopyruvate. The reaction mixture was refluxed overnight. Aftercooling to room temperature, the solid was filtered off and the filtratewas concentrated in vacuo. Flash chromatography on a Biotage Horizon®system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave thetitle compound as a yellow foam. LC/MS 365.3 (M+1).

Step C:1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazole-4-carboxylicacid. To a solution of 0.62 g (1.7 mmol) of the compound from Step B in10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture wasstirred at ambient temperature overnight. Hydrochloric acid (2.0 M) wasthen added to neutralize the reaction mixture. After removal of theorganic solvents in vacuo, dichloromethane (20 mL) was added and theorganic layer was separated. The aqueous layer was extracted withdichloromethane (10 mL), and the combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to yield the titlecompound as a yellow foam. LC/MS 337.3 (M+1).

Intermediate 31-(3-Ethoxyphenyl)-2-(4-fluorophenyl)-H-imidazole-4-carboxylic Acid

Step A: N-(3-Ethoxyphenyl)-4-fluorobenzenecarboximidamide. To a solutionof 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodiumbis(trimethylsilyl)amide in 5.0 mL of tetrahydrofuran at ambienttemperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and theresulting solution was stirred for 20 min. To this reaction mixture wasslowly added a solution of 0.48 g (4.0 mmol) of 4-fluorobenzonitrile in2.0 mL of tetrahydrofuran. The resulting mixture was stirred at ambienttemperature for 5 hrs and then poured into brine (25 mL) anddichloromethane (50 mL). The organic layer was separated and the aqueouslayer was extracted with dichloromethane (25 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated invacuo to yield the title compound as yellow solid which was used withoutfurther purification. LC/MS 259.2 (M+1).

Step B: Ethyl1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylate. To amixture of the compound from Step A and 0.80 g (9.5 mmol) of sodiumbicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) ofethyl bromopyruvate. The reaction mixture was refluxed overnight. Aftercooling to room temperature, the solid was filtered off and the filtratewas concentrated in vacuo. Flash chromatography on a Biotage Horizon®system (silica gel, 0 to 30% ethyl acetate in hexanes gradient then 30%ethyl acetate in hexanes) gave the title compound as a viscous yellowoil. LC/MS 355.3 (M+1).

Step C: 1-(3-Ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylicacid. To a solution of 0.67 g (1.9 mmol) of ethyl1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylate in 10mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirredat ambient temperature overnight. Hydrochloric acid (2.0 M) was thenadded to neutralize the reaction mixture. After removal of the organicsolvents in vacuo, dichloromethane (20 mL) was added and the organiclayer was separated. The aqueous layer was extracted withdichloromethane (10 mL), and the combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to yield the titlecompound as a pale yellow solid. LC/MS 327.2 (M+1).

Intermediate 41-(3-Ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazole-4-carboxylic Acid

Step A: N-(3-Ethoxyphenyl)-24-difluorobenzenecarboximidamide. To asolution of 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodiumbis(trimethylsilyl)amide in 10 mL of tetrahydrofuran at ambienttemperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and theresulting solution was stirred for 20 min. The reaction mixture wascooled to −78° C. and then was added 0.57 mL (4.0 mmol) of2,4-difluorobenzonitrile. The resulting mixture was stirred from −78° C.to ambient temperature for 5 hrs and then poured into brine (25 mL) anddichloromethane (50 mL). The organic layer was separated and the aqueouslayer was extracted with dichloromethane (25 mL). The combined organiclayers were dried over sodium sulfate, filtered and concentrated invacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0to 50% ethyl acetate in hexanes gradient) gave the title compound as ayellow oil. LC/MS 277.2 (M+1).

Step B: Ethyl1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazole-4-carboxylate. Toa mixture of 0.112 g (0.41 mmol) of the compound from Step A and 0.10 g(1.2 mmol) of sodium bicarbonate in 5 mL of 1,4-dioxane was added 0.10mL (0.80 mmol) of ethyl bromopyruvate. The reaction mixture was refluxedovernight. After cooling to room temperature, the solid was filtered offand the filtrate was concentrated in vacuo. Flash chromatography on aBiotage Horizon® system (silica gel, 0 to 50% ethyl acetate in hexanesgradient) gave the title compound as a viscous yellow oil. LC/MS 373.2(M+1).

Step C:1-(3-Ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazole-4-carboxylicacid. To a solution of 0.10 g (0.27 mmol) of ethyl1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazole-4-carboxylate in2 mL of tetrahydrofuran, 1 mL of water and 1 mL of methanol was added0.20 mL (1.0 mmol) of 5.0 M NaOH solution. The reaction mixture wasstirred at ambient temperature for 4 hrs. Hydrochloric acid (2.0 M) wasthen added to neutralize the reaction mixture. After removal of theorganic solvents in vacuo, dichloromethane (10 mL) was added and theorganic layer was separated. The aqueous layer was extracted withdichloromethane (5 mL), and the combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to yield the titlecompound as a yellow foam. LC/MS 345.0 (M+1).

Intermediate 51-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazole-4-carboxylicAcid

Step A: N-(3-Ethoxyphenyl)-2-fluoro-4-methylbenzenecarboximidamide. To asolution of 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodiumbis(trimethylsilyl)amide in 10 mL of tetrahydrofuran at ambienttemperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and theresulting solution was stirred for 20 min. To this reaction mixture wasadded 0.54 g (4.0 mmol) of 4-fluoro-4-methylbenzonitrile. The resultingmixture was stirred at ambient temperature for 3 hrs and then pouredinto brine (25 mL) and dichloromethane (50 mL). The organic layer wasseparated and the aqueous layer was extracted with dichloromethane (25mL). The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuo to yield the title compound as a palegreen solid, which was used without further purification. LC/MS 273.2(M+1).

Step B: Ethel1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazole-4-carboxylate.To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodiumbicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) ofethyl bromopyruvate. The reaction mixture was refluxed overnight. Aftercooling to room temperature, the solid was filtered off and the filtratewas concentrated in vacuo. Flash chromatography on a Biotage Horizon®system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave thetitle compound as a viscous yellow oil. LC/MS 369.2 (M+1).

Step C:1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methyl-phenyl)-1H-imidazole-4-carboxylicacid. To a solution of 0.81 g (2.2 mmol) of ethyl1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazole-4-carboxylatein 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol wasadded 1.0 mL (5.0 mmol) of 5.0 M NaOH solution. The reaction mixture wasstirred at ambient temperature overnight. Hydrochloric acid (2.0 M) wasthen added to neutralize the reaction mixture. After removal of theorganic solvents in vacuo, dichloromethane (20 mL) was added and theorganic layer was separated. The aqueous layer was extracted withdichloromethane (10 mL), and the combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to yield the titlecompound as a yellow foam. LC/MS 341.1 (M+1).

Intermediate 61-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylicAcid

Step A:N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-fluorobenzenecarboxamidine. To asolution of 2.39 g (15.8 mmol) of 1,4-benzodioxan-6-amine in 30 mL oftetrahydrofuran at ambient temperature was added 8.7 mL (17.4 mmol) of2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide and theresulting solution was stirred for 20 min. To this reaction mixture wasadded 1.91 g (15.8 mmol) of 4-fluorobenzonitrile all at once. Theresulting mixture was stirred at ambient temperature overnight and thenpoured into brine (50 mL) and dichloromethane (150 mL). The organiclayer was separated and the aqueous layer was extracted withdichloromethane (50 mL). The combined organic layers were dried oversodium sulfate; filtered and concentrated in vacuo to yield the titlecompound as yellow solid which was used without further purification.LC/MS 273.2 (M+1).

Step B: Ethyl1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylate.To a mixture of the compound from Step A and 4.0 g (48 mmol) of sodiumbicarbonate in 50 mL of 1,4-dioxane was added 3.0 mL (24 mmol) of ethylbromopyruvate. The reaction mixture was refluxed overnight. Aftercooling to room temperature, the solid was filtered off and the filtratewas concentrated in vacuo. Flash chromatography on a Biotage Horizon®system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave thetitle compound as yellow solid. LC/MS 369.1 (M+1).

Step C:1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylicacid. To a solution of 2.1 g (5.7 mmol) of ethyl1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylatein 20 mL of tetrahydrofuran, 1 0 mL of water and 1 0 mL of methanol wasadded 2.0 mL (10 mmol) of 5.0 M NaOH solution. The reaction mixture wasstirred at ambient temperature overnight. Hydrochloric acid (2.0 M) wasthen added to neutralize the reaction mixture. After removal of theorganic solvents in vacuo, dichloromethane (20 mL) was added and theorganic layer was separated. The aqueous layer was extracted withdichloromethane (10 mL), and the combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to yield the titlecompound as a pale yellow foam. LC/MS 341.0 (M+1).

Intermediate 7 Methyl 3-(1-piperazinyl)-2-naphthoate

Step A: 2-Naphthalenecarboxylic acid,3-{[(trifluoromethyl)sulfonyl]oxy}-methyl ester. To a solution of 5.01 g(24.1 mmol) of 2-naphthalenecarboxylic acid, 3-hydroxy-, methyl ester in240 mL anhydrous pyridine under nitrogen at −10° C. was added dropwise4.18 mL (25.2 mmol) of trifluoromethanesulfonic anhydride over 15minutes. The solution was allowed to warm to room temperature overnight,after which it was concentrated to remove some of the pyridine. Thecrude material was dissolved in ethyl acetate (50 mL), washed withsaturated sodium bicarbonate (50 mL), 0.5 M sodium bicarbonate (2×50 mL)and brine solution (50 mL) sequentially. The organic layer was driedover magnesium sulfate, filtered and concentrated to yield a redamorphous solid. The crude product was purified using a Biotage Horizon®system (2-10% ethyl acetate/hexanes mixture) to give the title compoundas a white solid. ¹H NMR (CDCl₃): δ 8.66 (s, 1H), 7.99 (d, J=8.0 Hz,1H), 7.89 (d J=8.2 Hz, 1H), 7.74 (s, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.63(t, J=7.5 Hz, 1H), 4.02 (s, 3H). LC/MS 335.1 (M+1).

Step B: tert-Butyl4-[3-(methoxycarbonyl)-2-naphthyl]piperazine-1-carboxylate. To asolution of 417 mg (2.24 mmol) of tert-butyl piperazine-1-carboxylate in15 mL anhydrous toluene was added 500 mg (1.49 mmol) of the compoundfrom Step A. The resulting solution was bubbled with nitrogen gas for 15min., and then purged under vacuum for 5 min. Next, 215 mg (2.24 mmol)of sodium tert-butoxide was added, and the system was again purged for 2min under vacuum. To this mixture was added 48 mg (0.089 mmol) of1,1′-bis(diphenylphosphino)-ferrocene and 42 mg (0.074 mmol) ofbis(dibenzylideneacetone) palladium, and the system was purged for 2 minunder vacuum. The resulting mixture was heated under nitrogen at 100° C.for 16 hrs, then taken up in anhydrous diethyl ether, and filteredthrough a plug of Celiteq®. The mixture was concentrated in vacuo toyield a red solid, which was purified using a Biotage Horizon® system(15-20% ethyl acetate/hexanes mixture) to give the title compound. ¹HNMR (CDCl₃): δ 8.30 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.73 (d, J=8.2 Hz,1H), 7.51 (t, J=8.0 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.32 (s, 1H), 3.96(s, 3H), 3.66 (br, 4H), 3.07 (br, 4H), 1.52 (s, 9H). LC/MS 371.3 (M+1).

Step C: Methyl 3-(1-piperazinyl)-2-naphthoate, trifluoroacetic acidsalt. To 185 mg (0.498 mmol) of the compound from Step B was added 10 mLdichloromethane and 2 mL trifluoroacetic acid. When the reaction wascomplete by LC-MS (18 h), the solution was concentrated in vacuo to givethe title compound as a yellow oil. LC/MS 271.3 (M+1).

Intermediate 8 Methyl 3-(1-piperazinyl)-1-naphthoate, TrifluoroaceticAcid Salt

Step A: Methyl 3-nitro-1-naphthoate. To a suspension of 22.0 g (0.101mol) of 3-nitro-1-napthalene-carboxylic acid (prepared according toprocedures in Duffy, K. J., et al., in J. Med. Chem. 2001, 44,3730-3745) in 1 L of anhydrous dichloromethane at 0° C. under anatmosphere of nitrogen was added 9.8 mL (0.11 mol) of oxalyl chloridefollowed by 0.80 mL (10 mmol) of anhydrous N,N-dimethylformamide. Thereaction mixture was allowed to gradually warm to ambient temperaturefor 3 h until gas evolution ceased. The resulting homogeneous solutionwas concentrated in vacuo to remove all volatiles. The residue was thendissolved in 1 L of anhydrous dichloromethane and 20 mL (0.51 mol) ofanhydrous methanol was added. After stirring for 1 h, the reaction wascarefully quenched with a saturated aqueous sodium bicarbonate solution(500 mL). The organic layer was separated and the aqueous layer wasextracted with dichloromethane (2×250 mL). The combined organic layerswere washed with brine (300 mL), dried over magnesium sulfate, filteredand concentrated in vacuo to yield the title compound as a pale yellowsolid, which was used without further purification. LC/MS 232.2 (M+1).

Step B: Methyl 3-amino-1-naphthoate. To 1.15 g (1.08 mmol) of 10%palladium on carbon was added a suspension of 11.6 g (50.0 mmol) of theabove methyl 3-nitro-1-naphthoate in 150 mL of anhydrous ethanol and 40mL of anhydrous dichloromethane. The resulting suspension was agitatedunder an atmosphere of hydrogen at 40 psi for 3 h during which time allsolids dissolved. The reaction mixture was filtered through a plug ofCelite®, which was subsequently washed with dichloromethane (300 mL).The combined filtrates were concentrated in vacuo to yield the titlecompound as a pale green gum which was used without furtherpurification. LC/MS 202.1 (M+1).

Step C: Methyl 3-bromo-1-naphthoate. A solution of 4.34 g (62.9 mmol) ofsodium nitrite in 40 mL of water was added dropwise to a 0° C. solutionof 11.5 g (57.2 mmol) of the above methyl 3-amino-1-naphthoate in 300 mLof ethanol and 60 mL of 48% aqueous hydrobromic acid while maintainingan internal reaction temperature below 10° C. After complete addition ofthe aqueous solution the resulting dark red reaction mixture was stirredat 0° C. for an additional 30 min. The cooled (0° C.) reaction mixturewas then added over 20 min. to a suspension of 8.21 g (57.2 mmol) ofcuprous bromide in 60 mL of ethanol and 60 mL of 48% aqueous hydrobromicacid heated to 95° C. After stirring for 30 min. the reaction mixturewas cooled to 0° C. and carefully partitioned between ethyl ether (250mL) and water (600 mL). The organic layer was separated and the aqueouslayer was extracted with ethyl ether (2×300 mL). The combined organiclayers were washed with brine (100 mL), dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was passed through aplug of silica gel eluting with 30% dichloromethane in hexanes and thefiltrate concentrated in vacuo. Flash chromatography on a Biotage®purification apparatus (silica gel, 7% dichloromethane/hexanes) yieldedthe title compound as a colorless solid. ¹H NMR (DMSO-d₆): δ 8.67 (d,J=8.4 Hz, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 8.02 (d, J=8.0 Hz, 1H),7.68-7.71 (m, 1H), 7.63-7.66 (t, J=7.6 Hz, 1H), 3.94 (s, 3H). LC/MS265.0 (M+1) and 267.0 (M+3).

Step D: tert-Butyl4-[4-(methoxycarbonyl-2-naphthyl]-1-piperazinecarboxylate. To 670 mg(2.53 mmol) of the compound from Step C and 517 mg (2.78 mmol) oftert-butyl 1-piperazinecarboxylate in a dry 50 mL flask was added 20 mLanhydrous dioxane. The system was purged for 5 min., and then flushedwith nitrogen. 1.23 g (3.80 mmol) of cesium carbonate was added to theflask, and the system was again purged for 5 min with nitrogen, thenflushed with nitrogen. Next, 60 mg (0.1 5 mmol) of2-dicyclohexylphosphino-2′(N,N-dimethylamino)biphenyl, and 73 mg (0.13mmol) of bis(dibenzylideneacetone)palladium were added, and the systemwas purged with nitrogen one last time. The reaction mixture was heatedat 85° C. under nitrogen for 24 h. After cooling to room temperature,the solution was filtered through Celite® and concentrated in vacuo toyield an orange oil, which was purified using a Biotage Horizon® system(10%-25% ethyl acetate in hexanes gradient) to give the title compound.LC/MS: 371.2 (M+1)

Step E: Methyl 3-(1-piperazinyl)-1-naphthoate trifluoroacetic acid salt.To 120 mg (0.324 mmol) of the compound from Step D was added 5 mLdichloromethane and 0.5 mL trifluoroacetic acid. When the reaction wascomplete by LC-MS (1 h), the solution was concentrated in vacuo. Theresulting oil was triturated with ethyl ether (3 mL) and filtered togive the title compound as a pale green solid. ¹H NMR (CD₃OD): δ 8.64(d, J=8.2 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.46(m, 3H), 3.98 (s, 3H), 3.54 (t, J=4.8 Hz, 4H), 3.43 (t, J=5.5 Hz, 4H).LC/MS 271.0 (M+1).

Intermediate 9 [(3-Bromo-1-naphthyl)methoxy](triisopropyl)silane

Step A: Methyl 3-nitro-1-naphthoate. To a suspension of 22.0 g (0.101mol) of 3-nitro-1-napthalene-carboxylic acid (prepared according toprocedures in Duffy, K. J., et. al. J. Med. Chem. 2001, 44, 3730-3745)in 1,000 mL of anhydrous dichloromethane at 0° C. under an atmosphere ofnitrogen was added 9.8 mL (0.11 mol) of oxalyl chloride followed by 0.80mL (10 mmol) of anhydrous N,N-dimethylformamide. The reaction mixturewas allowed to gradually warm to ambient temperature for 3 h until gasevolution ceased, and the resulting homogeneous solution wasconcentrated in vacuo to remove all volatiles. The residue was thendissolved in 1 L of anhydrous dichloromethane and 20 mL (0.51 mol) ofanhydrous methanol was added. After stirring for 1 h, the reaction wascarefully quenched with a saturated aqueous sodium bicarbonate solution(500 mL). The organic layer was separated and the aqueous layer wasextracted with dichloromethane (2×250 mL). The combined organic layerswere washed with brine (300 mL), dried over magnesium sulfate, filteredand concentrated in vacuo to yield the title compound as a pale yellowsolid which was used without further purification. LC/MS 232.2 (M+1).

Step B: Methyl 3-amino-1-naphthoate. To 1.15 g (1.08 mmol) of 10%palladium on carbon was added a suspension of 11.6 g (50.0 mmol) of theabove methyl 3-nitro-1-naphthoate in 150 mL of anhydrous ethanol and 40mL of anhydrous dichloromethane. The resulting suspension was agitatedunder an atmosphere of hydrogen at 40 psi for 3 h during which time allsolids dissolved. The reaction mixture was filtered through a plug ofCelite®, which was subsequently washed with dichloromethane (300 mL).The combined filtrates were concentrated in vacuo to yield the titlecompound as a pale green gum which was used without furtherpurification. LC/MS 202.1 (N+1).

Step C: Methyl 3-bromo-1-naphthoate. A solution of 4.34 g (62.9 mmol) ofsodium nitrite in 40 mL of water was added dropwise to a 0° C. solutionof 11.5 g (57.2 mmol) of methyl 3-amino-1-naphthoate in 300 mL ofethanol and 60 mL of 48% aqueous hydrobromic acid while maintaining aninternal reaction temperature below 10° C. After complete addition ofthe aqueous solution the resulting dark red reaction mixture was stirredat 0° C. for an additional 30 min. The cooled (0° C.) reaction mixturewas then added over 20 min. to a suspension of 8.21 g (57.2 mmol) ofcuprous bromide in 60 mL of ethanol and 60 mL of 48% aqueous hydrobromicacid heated to 95° C. After stirring for 30 min. the reaction mixturewas cooled to 0° C. and carefully partitioned between ethyl ether (250mL) and water (600 mL). The organic layer was separated and the aqueouslayer was extracted with ethyl ether (2×300 mL). The combined organiclayers were washed with brine (100 mL), dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was passed through aplug of silica gel eluting with 30% dichloromethane in hexanes and thefiltrate concentrated in vacuo. Flash chromatography on a Biotage®purification apparatus (silica gel, 7% dichloromethane/hexanes) yieldedthe title compound as a colorless solid. ¹H NMR (DMSO-d₆): δ 8.67 (d,J=8.4 Hz, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 8.02 (d, J=8.0 Hz, 1H),7.68-7.71 (m, 1H), 7.63-7.66 (t, J=7.6 Hz, 1H), 3.94 (s, 3H). LC/MS265.0 (M+1) and 267.0 (M+3).

Step D: (3-Bromo-1-naphthyl)methanol. To a solution of 5.10 g (19.2mmol) of the above methyl 3-bromo-1-naphthoate in 20 mL of anhydroustetrahydrofuran at −78° C. under an atmosphere of nitrogen was added 48mL (48 mmol) of a 1.0 M solution of diisobutylaluminum hydride intoluene. The resulting solution was allowed to gradually warm to 0° C.over 90 min and quenched with a saturated aqueous solution of potassiumsodium tartrate (25 mL). The resulting suspension was vigorously stirredwith gradual warming to ambient temperature over 2 h and the layersseparated. The aqueous layer was extracted with ethyl acetate (3×20 mL)and the combined organic layers were washed with brine (30 mL), driedover magnesium sulfate, filtered and concentrated in vacuo to afford thetitle compound as a white solid which was used without furtherpurification LC/MS 237.0 (M+1) and 239.0 (M+3).

Step E: [(3-Bromo-1-naphthyl)methoxy](triisopropyl)silane. To a solutionof 4.56 g (19.2 mmol) of (3-bromo-1-naphthyl)methanol in 10 mL ofanhydrous N,N-dimethylformamide was added 2.88 g (42.3 mmol) ofimidazole, 117 mg (0.962 mmol) of 4-(dimethylamino)pyridine and 4.5 mL(21 mmol) of triisopropylsilyl chloride. The resulting solution wasstirred at ambient temperature for 15 h, diluted with a saturatedaqueous ammonium chloride solution (100 mL) and extracted with ether(3×40 mL). The combined organic layers were washed with water (2×30 mL)then brine (25 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude residue was purified on a Biotage®purification apparatus (silica gel, 3% methylene chloride in hexanes) toyield intermediate 9 as a colorless oil. LC/MS 393.0 (M+1) and 395.0(M+3).

EXAMPLE 13-(4-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicAcid, Trifluoroacetic Acid Salt

Step A: Methyl3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoateTo a solution of 300 mg (0.932 mmol) of intermediate 1 in 10 mL ofanhydrous dichloromethane at 0° C. was added 0.075 mL (0.94 mmol) ofmethanesulfonyl chloride and 0.188 mL (2.33 mmol) of1-methyl-1H-imidazole. The solution was allowed to stir at 0° C. for 45min. 428 mg (0.885 mmol) of intermediate 8 was added to the solution,and the solution was allowed to warm to room temperature over 1 hr. Thesolution was poured into saturated sodium bicarbonate (10 mL) andextracted with dichloromethane (2×10 mL). The combined organic layerswere washed with brine (30 mL), dried over magnesium sulfate, andconcentrated in vacuo to yield a yellow foam. The crude product waspurified using a Biotage Horizon® system (40-80% ethyl acetate/hexanesmixture) to give the title compound as a pale yellow foam. LC/MS: 574.2(M+1).

Step B:3-(4-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid trifluoroacetic acid salt To 480 mg (0.890 mmol) of the compoundfrom Step A in 6 mL of tetrahydrofuran and 3 mL of methanol was added3.5 mL (3.5 mmol) of 1 M lithium hydroxide solution. When the reactionwas complete by LC-MS (2 h) the solution was partitioned between 1 Nhydrochloric acid solution (10 mL) and ethyl acetate (100 mL). Theorganic layer was separated, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo to afford a yellowoil. This material was taken up in N,N-dimethylformamide (2 mL) andacetonitrile (1 mL) and purified by reverse phase HPLC (TMC Pro-Pac C18;30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroaceticacid in water gradient). The pure fractions were lyophilized overnightto give the title compound as a yellow solid. ¹H NMR (DMSO-d₆): δ 8.62(d, J=8.5 Hz, 1H), 7.98 (s, 2H), 7.81 (d, J=8.2 Hz, 1H), 7.48 (s, 1H),7.46 (t, J=7.8 Hz, 1H), 7.35 (m, 2H), 7.26 (d, J=7.6 Hz, 2H), 7.16 (d,J=7.8 Hz, 2H), 7.00 (t, J=8.4 Hz, 1H), 6.99 (s, 1H), 6.83 (d, J=7.8 Hz,1H), 4.48 (br, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.85 (br, 2H), 3.38 (s, 4H),2.29 (s, 3H), 1.27 (t, J=6.8 Hz, 3H). LC/MS 561.1 (M+1).

EXAMPLE 23-(4-{[1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicAcid, Trifluoroacetic Acid Salt

Step A: Methyl3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoateTo a solution of 200 mg (0.588 mmol) of intermediate 5 in 6 mL ofanhydrous dichloromethane at 0° C. was added 0.047 mL (0.59 mmol) ofmethanesulfonyl chloride and 0.118 mL (1.47 mmol) of1-methyl-1H-imidazole. The solution was allowed to stir at 0° C. for 45min. 215 mg (0.559 mmol) of intermediate 8 was added to the solution,and the solution was allowed to warm to room temperature over 1 hr. Thesolution was poured into saturated sodium bicarbonate (10 mL) andextracted with dichloromethane (2×10 mL). The combined organic layerswere washed with brine (30 mL), dried over magnesium sulfate, andconcentrated in vacuo to yield a yellow foam. The crude product waspurified using a Biotage Horizon® system (40-80% ethyl acetate/hexanesmixture) to give the title compound as a pale yellow foam. LC/MS: 593.2(M+1).

Step B:3-(4-{[1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid, trifluoroacetic acid salt To 480 mg (0.890 mmol) of the compoundfrom Step A in 6 mL of tetrahydrofuran and 3 mL of methanol was added3.5 mL (3.5 mmol) of 1 M lithium hydroxide solution. When the reactionwas complete by LC-MS (2 h) the solution was partitioned between 1 Nhydrochloric acid solution (10 mL) and ethyl acetate (100 mL). Theorganic layer was separated, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo to afford a yellowoil. This material was taken up in N,N-dimethylformamide (2 mL) andacetonitrile (1 mL) and purified by reverse phase HPLC (TMC Pro-Pac C18;30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroaceticacid in water gradient). The pure fractions were lyophilized overnightto give the title compound as a pale yellow solid. ¹H NMR (CD₃OD): δ8.72 (d, J=8.4 Hz, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.79 (d, J=8.2 Hz,1H), 7.43 (m, 4H), 7.32 (t, J=8.3 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 7.00(m, 2H), 6.87 (m, 2H), 4.27 (br, 2H), 4.03 (br, 2H), 3.96 (q, J=7.1 Hz,2H), 3.44 (s, 4H), 2.39 (s, 3H), 1.32 (t, J=6.8 Hz, 3H). LC/MS 579.1(M+1).

EXAMPLE 33-(4-{[1-(3-Ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicAcid, Trifluoroacetic Acid Salt

Step A: Methyl3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoate,trifluoroacetic acid salt To a solution of 59 mg (0.18 mmol) ofintermediate 3 and 70 mg (0.13 mmol) of intermediate 8 in 2 mL ofN,N-dimethylformamide was added 39 mg (0.20 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, 27 mg (0.20mmol) of 1-hydroxybenzotriazole, and 0.079 mL (0.45 mmol) ofdiisopropylethylamine. The solution was allowed to stir at roomtemperature overnight. The reaction was quenched with 0.01%trifluoroacetic acid in water (1.0 mL), and the reaction mixture waspurified directly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were concentrated in vacuo to yield ayellow residue. LC/MS 579.2 (M+1).

Step B:3-(4-{[1-(3-Ethoxyphenyl)-2-(4-fluoro-phenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid, trifluoroacetic acid salt To 65 mg (0.11 mmol) of the compoundfrom Step A in 3 mL of tetrahydrofuran and 1.5 mL of methanol was added1 mL (1 mmol) of 1 M lithium hydroxide solution. When the reaction wascomplete by LC-MS (2 h) the solution was partitioned between 1 Nhydrochloric acid solution (10 mL) and ethyl acetate (100 mL). Theorganic layer was separated, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo to afford a yellowoil. This material was taken up in N,N-dimethylformamide (1 mL) andacetonitrile (0.5 mL) and purified by reverse phase HPLC (TMC Pro-PacC18; 30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01%trifluoroacetic acid in water gradient). The pure fractions werelyophilized overnight to give the title compound as a yellow solid. ¹HNMR (CD₃OD): δ 8.71 (d, J=8.5 Hz, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.91 (s,1H), 7.79, (d, J=8.2 Hz, 1H), 7.45, (m, 4H), 7.36 (m, 2H), 7.10 (m, 2H),7.03 (dd, J=8.3 Hz, 1.9 Hz, 1H), 6.88 (m, 2H), 4.39 (br, 2H), 4.02 (br,2H), 3.98 (q, J=7.1 Hz, 2H), 3.43 (t, J=35.0 Hz, 4H), 1.33 (t, J=6.9 Hz,3H). LC/MS 565.1 (M+1).

EXAMPLE 43-(4-{[1-(3-Ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicAcid, Trifluoroacetic Acid Salt

Step A: Methyl3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoateTo a solution of 21 mg (0.061 mmol) of intermediate 4 in 2 mL ofanhydrous dichloromethane at 0° C. was added 0.005 mL (0.06 mmol) ofmethanesulfonyl chloride and 0.012 mL (0.15 mmol) of1-methyl-1H-imidazole. The solution was allowed to stir at 0° C. for 45min. 23 mg (0.061 mmol) of intermediate 8 was added to the solution, andthe solution was allowed to warm to room temperature over 1 hr. Thesolution was poured into saturated sodium bicarbonate (5 mL) andextracted with dichloromethane (2×5 mL). The combined organic layerswere washed with brine (20 mL), dried over magnesium sulfate, andconcentrated in vacuo to yield a yellow foam. The crude product waspurified using a Biotage Horizon® system (40-80% ethyl acetate/hexanesmixture) to give the title compound as a pale yellow foam. LC/MS: 597.1(M+1).

Step B:3-(4-{[1-(3-Ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid, trifluoroacetic acid salt To 30 mg (0.050 mmol) of the compoundfrom Step A in 3 mL of tetrahydrofuran and 1.5 mL of methanol was added1 mL (1 mmol) of 1 M lithium hydroxide solution. When the reaction wascomplete by LC-MS (2 h) the solution was partitioned between 1 Nhydrochloric acid solution (5 mL) and ethyl acetate (50 mL). The organiclayer was separated, washed with brine (50 mL), dried over magnesiumsulfate, filtered and concentrated in vacuo to afford a yellow oil. Thismaterial was taken up in N,N-dimethylformamide (1 mL) and acetonitrile(1 mL) and purified by reverse phase HPLC (TMC Pro-Pac C18; 30-100%0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid inwater gradient). The pure fractions were lyophilized overnight to givethe title compound as a yellow solid. ¹H NMR (DMSO-d₆): δ 8.62 (d, J=8.5Hz, 1H), 8.10 (s, 1H), 7.97 (d, J=2.5 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H),7.66 (q, J=8.5 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H),7.37 (t, J=8.0 Hz, 1H), 7.28 (m, 2H), 7.21 (dt, J=8.6 Hz, 2.7 Hz, 1H),6.94 (dd, J=8.5 Hz, 2.5 Hz, 1H), 6.89 (t, J=2.0 Hz, 1H), 6.77 (dd, J=8.0Hz, 1.8 Hz, 1H), 4.43 (br, 2H), 3.96 (q, J=7.1 Hz, 2H), 3.83 (br, 2H),3.36 (t, J=4.8 Hz, 4H), 1.25 (t, J=6.8 Hz, 3H). LC/MS 583.1 (M+1).

EXAMPLE 53-(4-{[1-(3-Ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoicAcid, Trifluoroacetic Acid Salt

Step A: Methyl3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoatetrifluoroacetic acid salt To a solution of 42 mg (0.13 mmol) ofintermediate 3 and 50 mg (0.13 mmol) of intermediate 7 in 2 mL ofN,N-dimethylformamide was added 28 mg (0.14 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, 19 mg (0.14mmol) of 1-hydroxybenzotriazole, and 0.079 mL (0.45 mmol) ofdiisopropylethylamine. The solution was allowed to stir at roomtemperature overnight. The reaction was quenched with 0.01%trifluoroacetic acid in water (1.0 mL), and the reaction mixture waspurified directly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were concentrated in vacuo to yield ayellow residue. LC/MS 579.3 (M+1).

Step B:3-(4-{[1-(3-Ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoicacid, trifluoroacetic acid salt To 50 mg (0.072 mmol) of the compoundfrom Step A in 3 mL of tetrahydrofuran and 1.5 mL of methanol was added1 mL (1 mmol) of 1 M lithium hydroxide solution. When the reaction wascomplete by LC-MS (2 h) the solution was partitioned between 1 Nhydrochloric acid solution (10 mL) and ethyl acetate (100 mL). Theorganic layer was separated, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo to afford a yellowoil. This material was taken up in N,N-dimethylformamide (1 mL) andacetonitrile (0.5 mL) and purified by reverse phase HPLC (TMC Pro-PacC18; 30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01%trifluoroacetic acid in water gradient). The pure fractions werelyophilized overnight to give the title compound as a yellow solid. ¹HNMR (CD₃OD): δ 8.79 (s, 1H), 8.17 (s, 1H), 8.05 (d, J=8.4 Hz, 1H), 8.04(s, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.68 (dt J=6.8 Hz, 0.9 Hz, 1H), 7.62(dt, 8.0 Hz, 1.2 Hz, 1H), 7.46 (m, 2H), 7.38 (t, J=8.3 Hz, 1H), 7.11 (t,J=8.7 Hz, 1H), 7.05 (dd, J=8.4 Hz, 2.5 Hz, 1H), 6.90 (m, 2H), 4.39 (br,4H), 3.98 (q, J=7.1 Hz, 2H), 3.52 (t, J=5.1 Hz, 4H), 1.33 (t, J=7.1 Hz,3H). LC/MS 565.3 (M+1).

EXAMPLE 63-(4-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoicAcid, Trifluoroacetic Acid Salt

Step A: Methyl3-(4-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoate,trifluoroacetic acid salt To a solution of 90 mg (0.28 mmol) ofintermediate 1 and 118 mg (0.308 mmol) of intermediate 7 in 3 mL ofN,N-dimethylformamide was added 59 mg (0.302 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, 41 mg(0.302 mmol) of 1-hydroxybenzotriazole, and 0.158 mL (0.906 mmol) ofdiisopropylethylamine. The solution was allowed to stir at roomtemperature overnight. The reaction was quenched with 0.01%trifluoroacetic acid in water (2.0 mL), and the reaction mixture waspurified directly by reverse phase HPLC (TMC Pro-Pac C18, 30-100% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were concentrated in vacuo to yield ayellow residue. LC/MS 575.2 (M+1).

Step B:3-(4-{[1-(3-Ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoicacid trifluoroacetic acid salt To 80 mg (0.14 mmol) of the compound fromStep A in 3 mL of tetrahydrofuran and 1.5 mL of methanol was added 1 mL(1 mmol) of 1 M lithium hydroxide solution. When the reaction wascomplete by LC-MS (2 h) the solution was partitioned between 1 Nhydrochloric acid solution (10 mL) and ethyl acetate (100 mL). Theorganic layer was separated, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo to afford a yellowoil. This material was taken up in NAN-dimethylformamide (1 mL) andacetonitrile (0.5 mL) and purified by reverse phase HPLC (TMC Pro-PacC18; 30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01%trifluoroacetic acid in water gradient). The pure fractions werelyophilized overnight to give the title compound as a yellow solid. ¹HNMR (DMSO-d₆): δ 8.92 (s, 1H), 7.99 (t, J=8.2 Hz, 1H), 7.97 (s, 1H),7.86 (d, J=8.3 Hz, 1H), 7.70 (s, 1H), 7.65 (dt, J=6.9 Hz, 1.0 Hz, 1H),7.60 (dt, J=8.3 Hz, 1.2 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.31 (d, J=8.2Hz, 2H), 7.26 (s, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.01 (dd, J=7.8 Hz, 1.7Hz, 1H), 6.80 (d, J=6.0 Hz, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.38 (br, 8H),1.39 (t, J=6.9 hz, 3H). LC/MS 561.3 (M+1).

EXAMPLE 71-O-[3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl-1-naphthoyl]hexopyranuronicAcid

Step A: Allyl6-{[3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazo-4-yl]carbonyl}piperazin-1-yl)-1-naphthoyl]oxy}-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylateTo a mixture of 0.312 g (0.558 mmol) of Example 1, 0.176 g (0.670 mmol)of triphenylphosphine and 0.157 g (0.670 mmol) of allyl glucuronate(synthesized according to Helene Juteau et al, Tetrahedron Lett. 1997,38, 1481-1484) in 5 ml of N,N-dimethylformamide at 0° C. was added 0.13ml (0.67 mmol) of diisopropyl azodicarboxylate dropwise. The reactionmixture was allowed to stir from 0° C. to ambient temperature overnight.Then 0.088 g ((0.34 mmol) of triphenylphosphine and 0.065 ml (0.34 mmol)of diisopropyl azodicarboxylate was added again and the reaction mixturewas stirred at ambient temperature for an additional 4 hours. Thesolvent was removed under high vacuum at ambient temperature and theresidue was purified on a Biotage Horizon® system (silica gel, 50 to100% ethyl acetate in hexanes gradient then ethyl acetate). The mixturewas further purified on preparative TLC (silica gel, 7.5% methanol indichloromethane) to yield a mixture of α and β isomers. Chiral HPLCseparation (Chiralcel OD, 55% 2-propanol/heptane) afforded αdiastereomer (first eluting) and β diastereomer (second eluting).

Step B:1-O-[3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoyl]hexopyranuronicacid A portion of 6.5 mg (0.0084 mmol) of the product from Step A (βisomer) and 1.0 mg (0.0071 mmol) of 5,5-dimethyl-1,3-cyclohexanedione in0.5 ml of tetrahydrofuran at ambient temperature was added 0.5 mg(0.0004 mmol) of tetrakis(triphenyl-phosphine)palladium(0). The reactionmixture was stirred at ambient temperature for 2 hours and then passedthrough a plug of silica gel eluting with 10% methanol indichloromethane. The filtrate was concentrated in vacuo and residue waspurified by reverse phase HPLC (TMC Pro-Pac C18; 10-80% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were lyophilized overnight to give thetitle compound as a yellow solid. ¹H NMR (DMSO-d₆): δ 8.59 (d, J=8.7 Hz,1H), 8.10 (d, J=2.6 Hz, 1H), 7.95 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.58(d, J=2.0 Hz, 1H), 7.50 (t, J=7.3 Hz, 1H), 7.42 (t, J=7.2 Hz, 1H), 7.35(t, J=8.1 Hz, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H),7.02-6.97 (m, 2H), 6.83 (d, J=7.6 Hz, 1H), 5.73 (d, J=7.8 Hz, 1H), 4.50(br s), 4.01 (q, J=7.1 Hz, 2H), 3.95-3.82 (m, 3H), 3.47-3.40 (m), 2.29(s, 3H), 1.28 (t, J=7.1 Hz, 3H). LC/MS 737.2 (M+1).

EXAMPLE 8N-[3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoyl]-D-asparticAcid

Step A: DibenzylN-[3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoyl]-D-asparticacid, trifluoroacetic acid salt To a solution of 30 mg (0.054 mmol) ofexample 1 and 16 mg (0.054 mmol) of D-aspartic acid in 2 mL ofN,N-dimethylformamide was added 11 mg (0.059 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, 9 mg (0.06mmol) of 1-hydroxybenzotriazole, and 0.028 mL (0.16 mmol) ofdiisopropylethylamine. The solution was allowed to stir at roomtemperature overnight. The reaction was quenched with 0.01%trifluoroacetic acid in water (1.0 mL), and the reaction mixture waspurified directly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were concentrated in vacuo to yield ayellow residue. LC/MS 856.4 (M+1).

Step B:N-[3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoyl]-D-asparticacid, trifluoroacetic acid salt A solution of 12 mg (0.014 mmol) of theproduct of Step A in 2 mL of methanol was purged under vacuum andbackfilled with nitrogen. To this inert atmosphere was added 30 mg(0.028 mmol) of palladium on carbon, 10% by weight. The mixture waspurged under vacuum and backfilled with nitrogen. The system was purgedwith hydrogen, and allowed to stir at room temperature under hydrogenfor 30 min. The mixture was filtered through Celite©, washed withmethanol (5 mL) and concentrated. The residue was dissolved inN,N-dimethylformamide and purified directly by reverse phase HPLC (TMCPro-Pac C18; 30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01%trifluoroacetic acid in water gradient) the pure fractions werelyophilized to yield a white solid. ¹H NMR (CD₃OD): δ 8.12 (d, J=8.5 Hz,1H), 8.04 (s, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.43(m, 1H), 7.38 (m, 1H), 7.33 (m, 4H), 7.22 (m, 2H), 7.05 (d, J=8.5 Hz,1H), 6.91 (m, 2H), 5.05 (dd, J=7.8, 4.8 Hz, 1H), 4.28 (br, 2H), 4.01(br, 2H) 3.98 (q, J=7.1 Hz, 2H), 3.43 (br, 4H), 3.07 (d, J=5.0 Hz,0.5H), 3.04 (J=5.0 Hz, 0.5H), 2.94 (d, J=8.0 Hz, 0.5H), 2.91 (d, J=8.0Hz, 0.5H), 2.35 (s, 3H), 1.33 (t, J=6.8 Hz, 3H). LC/MS 676.1 (M+1).

The compounds in Table 1 were prepared using the appropriate startingmaterials and reagents following procedures similar to those describedabove for Examples 1-6:

TABLE 1

Example R¹⁰ R² R³ R⁴ R⁵ R⁶ R⁷ MS (M + 1)  9 7-MeO OMe H H H Me H 533.310 3-CO₂H OMe H H H Me H 547.2 11 1-CO₂Me OMe H H H Me H 561.2 12 5-CO₂HOEt H H H Me H 561.3 13 4-CONHi-Pr OEt H H H Me H 602.4 14

OEt H H H Me H 614.4 15 4-CONHEt OEt H H H Me H 588.3 16 4-CON(Et)₂ OEtH H H Me H 616.3 17 3-CON(Et)₂ OEt H H H Me H 616.2 18

OEt H H H Me H 614.2 19 3-CONHEt OEt H H H Me H 588.2 20 3-C(O)NHi-PrOEt H H H Me H 602.2 21 3-CO₂H OEt H H H F F 583.2 22 4-CO₂H OH H H H MeH 533.5 23 4-CO₂H OMe H H H Me H 547.2 24 4-CO₂H OEt H H H H H 547.3 254-CO₂H OEt H H H Cl H 581.3 26 3-CO₂H OEt H H F Me H 579.2 27 4-CN OEt HH H Me H 542.2 28 4-NHSO₂Me OEt H H H Me H 610.0 29 4-NHSO₂i-Pr OEt H HH Me H 638.1 30 4-NH₂ OEt H H H Me H 532.2 31

OEt H H H Me H 585.0 32

OEt H H H Me H 737.2 33

OEt H H H Me H 722.3 34 4-CO₂H OEt H H H CH₂OH H 577.2 354-trans-CHCHCO₂H OEt H H H Me H 587.1 36 4-CH₂CH₂CO₂H OEt H H H Me H589.1 37

OEt H H H Me H 634.2 38

OEt H H H Me H 724.2 39

OEt H H H Me H 722.2 40

OEt H H H Me H 672.2 41

OEt H H H Me H 662.2 42

OEt H H H Me H 634.6 43

OEt H H H Me H 690.6 44

OEt H H H Me H 634.2 45

OEt H H H Me H 690.2 46

OEt H H H Me H 676.1 47

OEt H H H Me H 648.1 48 —CH₂CO₂H OEt H H H Me H 575.3

EXAMPLE 49 3-(4-{[1-(2,3-Dihydro-14-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicAcid, Trifluoroacetic Acid Salt

Step A: Methyl3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoate,trifluoroacetic acid salt To a solution of 62 mg (0.18 mmol) ofintermediate 3 and 70 mg (0.13 mmol) of intermediate 8 in 2 mL ofN,N-dimethylformamide was added 39 mg (0.20 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, 27 mg (0.20mmol) of 1-hydroxybenzotriazole, and 0.079 mL (0.45 mmol) ofdiisopropylethylamine. The solution was allowed to stir at roomtemperature overnight. The reaction was quenched with 0.01%trifluoroacetic acid in water (1.0 mL), and the reaction mixture waspurified directly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were concentrated in vacuo to yield ayellow residue. LC/MS 593.2 (M+1).

Step B:3-(4-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid, trifluoroacetic acid salt To 85 mg (0.11 mmol) of the compoundfrom Step A in 3 mL of tetrahydrofuran and 1.5 mL of methanol was added1 mL (1 mmol) of 1 M lithium hydroxide solution. When the reaction wascomplete by LC-MS (2 h) the solution was partitioned between 1 Nhydrochloric acid solution (10 mL) and ethyl acetate (100 mL). Theorganic layer was separated, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo to afford a yellowoil. This material was taken up in N,N-dimethylformamide (1 mL) andacetonitrile (0.5 mL) and purified by reverse phase HPLC (TMC Pro-PacC18; 30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01%trifluoroacetic acid in water gradient). The pure fractions werelyophilized overnight to give the title compound as a yellow solid. ¹HNMR (DMSO-d₆): δ 8.62 (d, J=8.5 Hz, 1H), 7.97 (d, J=2.3 Hz, 1H), 7.87(s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.43 (m, 4H), 7.38 (t. J=8.0 Hz, 1H),7.21 (m, 2H), 6.98 (d, J=2.3 Hz, 1H), 6.93 (d, J=8.7 Hz, 1H), 6.78 (dd,J=8.5 Hz, 2.6 Hz, 1H), 4.46 (br, 2H), 4.27 (s, 4H), 3.84 (br, 2H), 3.37(t, J=4.7 Hz, 4H). LC/MS 579.2 (M+1).

EXAMPLE 503-(4-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicAcid, Hydrochloride Salt

Step A: Methyl 3-(4-{[1-(2,3-Dihydro1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid trifluoroacetic acid salt To a solution of 70 mg (0.21 mmol) ofintermediate 2 and 80 mg (0.21 mmol) of intermediate 8 in 3 mL ofN,N-dimethylformamide was added 45 mg (0.23 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarboiimide hydrochloride, 31 mg (0.23mmol) of 1-hydroxybenzotriazole, and 0.127 mL (0.723 mmol) ofdiisopropylethylamine. The solution was allowed to stir at roomtemperature overnight. The reaction was quenched with 0.01%trifluoroacetic acid in water (1.0 mL), and the reaction mixture waspurified directly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were concentrated in vacuo to yield ayellow residue.

Step B:3-(4-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-piperazinyl)-1-naphthoicacid, hydrochloride salt. To 50 mg (0.071 mmol) of the compound fromStep A in 3 mL of tetrahydrofuran and 1.5 mL of methanol was added 1 mL(1 mmol) of 1 M lithium hydroxide solution. When the reaction wascomplete by LC-MS (2 h) the solution was partitioned between 1 Nhydrochloric acid solution (10 mL) and ethyl acetate (100 mL). Thecompound precipitated out, was filtered, washed with water, and dried onthe hi-vac overnight. The resultant yellow compound was the purechloride salt. ¹H NMR (DMSO-d₆): δ 8.62 (d, J=8.7 Hz, 1H), 7.97 (d,J=6.5 Hz, 1H), 7.82 9s, 1H), 7.81 (d, J=9.6 Hz, 1H), 7.46 (m, 2H), 7.37(t, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 6.95(d, J=2.5 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.76 (dd, J=8.7 Hz, 2.5 Hz,1H), 4.49 (br, 2H), 4.27 (s, 4H), 3.84 (br, 2H), 3.36 (t, J=4.8 Hz, 4H),2.92 (s, 3H). LC/MS 575.4 (M+1).

EXAMPLE 513-(4-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoicAcid, Trifluoroacetic Acid Salt

Step A: Methyl3-(4-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoate,trifluoroacetic acid salt. To a solution of 346 mg (1.03 mmol) ofintermediate 2 and 438 mg (1.14 mmol) of intermediate 7 in 10 mL ofN,N-dimethylformamide was added 200 mg (1.114 mmol) ofN-(3-dimethyl-aminopropyl)-N′-ethylcarboiimide hydrochloride, 153 mg(1.14 mmol) of 1-hydroxybenzotriazole, and 0.716 mL (4.12 mmol) ofdiisopropylethylamine. The solution was stirred at room temperatureovernight. The reaction was quenched with 0.01% trifluoroacetic acid inwater (2 mL), and the reaction mixture was purified directly by reversephase HPLC (TMC Pro-Pac C18; 30-100% 0.01% trifluoroacetic acid inacetonitrile/0.01% trifluoroacetic acid in water gradient). The purefractions were lyophilized overnight to yield a yellow solid.

Step B:3-(4-{[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-2-naphthoicacid, trifluoroacetic acid salt To a solution of the compound from StepA in 10 mL of tetrahydrofuran was added 2 mL of methanol and 2 mL (2.0mmol) 1M lithium hydroxide solution. When the reaction was complete byLC-MS (2 h) the solution was partitioned between 1 N hydrochloric acid(10 mL) and ethyl acetate (100 mL). The organic layer was separated,washed with brine (50 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo to afford a yellow oil. This material was taken upin acetonitrile, filtered, and purified by reverse phase HPLC (TMCPro-Pac C18; 30-100% 0.01% trifluoroacetic acid in acetonitrile/0.01%trifluoroacetic acid in water gradient). The pure fractions werelyophilized overnight to give the title compound as a yellow solid. ¹HNMR (CD₃OD): δ 8.76 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 8.03 (d, J=8.5Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.66 (dt, J=7.1 Hz, 1.2 Hz, 1H), 7.60(dt, J=8.0 Hz, 0.9 Hz, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.0 Hz,2H) 6.92 (m, 2H), 6.82 (dd, J=9.5 Hz, 2.6 Hz, 1H), 4.23 (q, J=3.9 Hhz,4H), 4.23 (br, 4H), 3.43 (t, J=5.1 Hz, 4H), 2.34 (s, 3H). LC/MS 575.3(M+1).

The compounds in Table 2 were prepared using the appropriate startingmaterials and reagents following procedures similar to those describedabove for Examples 24-26:

TABLE 2

Example R¹⁰ R⁶ R⁷ X MS (M + 1) 52 4-CO₂H Me F N 593.3 52 3-CO₂H F H N579.2 54 4-CO₂H Me H CH 574.2 55 4-CO₂H Me H CNH₂ 588.9

EXAMPLE 563-(1-{[1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperidin-4-yl)-1-naphthoicAcid, Trifluoroacetic Acid Salt

Step A: tert-Butyl4-hydroxy-4-(4-{[(triisopropylsilyl)oxy]methyl}-2-naphthyl)piperidine-1-carboxylate.To a solution of 1.30 g (3.30 mmol) of intermediate 9 in 5 mL ofanhydrous tetrahydrofuran at −78° C. under an atmosphere of nitrogen wasadded 2.6 mL (3.6 mmol) of a 1.4 M sec-butyl lithium solution incyclohexane. After stirring for 1.5 h, a solution of 731 mg (3.67 mmol)of tert-butyl 4-oxopiperidine-1-carboxylate in 5 mL of anhydroustetrahydrofuran at −78° C. was added under nitrogen. The reactionmixture was then allowed to gradually warm to ambient temperature,stirred for an additional 1 h, and then diluted with a saturated aqueousammonium chloride solution (25 mL). The layers were separated and theaqueous phase was extracted with ethyl acetate (3×25 mL). The combinedorganic layers were washed with brine (25 mL), dried over magnesiumsulfate, filtered and evaporated in vacuo. The crude residue waspurified on a Biotage® purification apparatus (silica gel, 35% ethylacetate in hexanes) to yield the title compound as a colorless oil.LC/MS 536.5 (M+23).

Step B: tert-Butyl4-hydroxy-4-[4-(hydroxymethyl)-2-naphthyl]piperidine-1-carboxylate. To asolution of 1.30 g (2.53 mmol) of tert-butyl4-hydroxy-4-(4-{[(triisopropylsilyl)oxy]methyl}-2-naphthyl)-iperidine-1-carboxylatein 20 mL of tetrahydrofuran was added 5.1 mL (5.1 mmol) of a 1.0 Msolution of tetrabutylammonium fluoride in tetrahydrofuran. Afterstirring for 30 min the reaction was diluted with a saturated aqueoussodium bicarbonate solution (15 mL), the layers separated, and theaqueous phase extracted with ethyl acetate (3×10 mL). The combinedorganic layers were washed with water (5 mL), brine (5 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo to yield the crudetitle compound as a colorless oil. LC/MS 380.2 (M+23).

Step C: tert-Butyl4-(4-formyl-2-naphthyl)-4-hydroxypiperidine-1-carboxylate. To a solutionof 1.0 g (2.8 mmol) of tert-butyl4-hydroxy-4-[4-(hydroxymethyl)-2-naphthyl]piperidine-1-carboxylate in 10mL of anhydrous dichloromethane under an atmosphere of nitrogen wasadded 0.34 mL (4.2 mmol) of pyridine then 1.9 g (4.5 mmol) ofDess-Martin periodinane and the resulting solution was stirred atambient temperature for 2 h. The mixture was diluted with a saturatedaqueous sodium bicarbonate solution (5 mL), the layers were separatedand the aqueous phase extracted with dichloromethane (3×10 mL). Thecombined organic layers were washed with brine (25 mL), dried overmagnesium sulfate, filtered and evaporated in vacuo to yield the crudetitle compound as a colorless oil.

Step D: 3-[1-(tert-Butoxycarbonyl)-4-hydroxypiperidin-4-yl]-1-naphthoicacid. To a solution of 1.5 g (4.2 mmol) of tert-butyl4-(4-formyl-2-naphthyl)-4-hydroxypiperidine-1-carboxylate in 25 mL of2-methyl-2-propanol was added 2.3 mL (21 mmol) of 2-methyl-2-butenefollowed by dropwise addition of a solution of 1.00 g (8.45 mmol) ofsodium dihydrogen phosphate and 877 mg (59.7 mmol) of sodium chlorite in15 mL of water. The resulting mixture was stirred at ambient temperaturefor 2 h then evaporated in vacuo to remove all volatiles. The residuewas diluted with water (5 mL) and an aqueous 2 N HCl solution was thenadded dropwise to the stirred mixture until a pH of 4 was achieved. Theaqueous phase was then extracted with ethyl acetate (3×5 mL) and thecombined organic layers were washed with brine (25 mL), dried overmagnesium sulfate, filtered and evaporated in vacuo to yield the crudetitle compound as a colorless oil. LC/MS 394.2 (M+23).

Step E: tert-Butyl4-hydroxy-4-[4-(methoxycarbonyl)-2-naphthyl]piperidine-1-carboxylate. Toa solution of 1.3 g (3.5 mmol) of the above3-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl]-1-naphthoic acid in10 mL of methanol and 10 mL of ether was added 2.0 mL (4.0 mmol) of a2.0 M solution of (trimethylsilyl)diazomethane in ether. Glacial aceticacid was the added dropwise until gas evolution ceased and then thereaction was concentrated in vacuo to yield the crude title compound asa yellow oil. LC/MS 408.1 (M+23).

Step F: Methyl 3-(1,2,3,6-tetrahydropyridin-4-yl)-1-naphthoate,trifluoroacetic acid salt. To a solution of 104 mg (0.269 mmol) oftert-butyl4-hydroxy-4-[4-(methoxycarbonyl)-2-naphthyl]piperidine-1-carboxylate in2.0 mL of dichloromethane was added 2.0 mL of trifluoroacetic acid andthe resulting mixture was heated to 40° C. for 4 h. The reaction mixturewas then concentrated in vacuo to yield the crude title compound as ayellow oil. LC/MS 268.1 (M+1).

Step G: Methyl 3-piperidin-4-yl-1-naphthoate, trifluoroacetic acid salt.To 100 mg (0.370 mmol) of methyl3-(1,2,3,6-tetrahydropyridin-4-yl)-1-naphthoate, trifluoroacetic acidsalt was added 3 mL of methanol and the system was purged with nitrogen.Next, 10 mg of palladium hydroxide (20 wt. % Pd (dry basis) on carbon)was added, and the system was again purged with nitrogen. The flask wasthen carefully purged with hydrogen and the reaction mixture was allowedto stir for 45 min at room temperature under 1 atmosphere of hydrogengas until the reaction was complete by LC-MS. After purging the systemwith nitrogen, the solution was carefully filtered through a Celite®plug to remove the palladium and then rinsed with methanol (10 mL). Thefiltrate was concentrated in vacuo to yield the title compound as ayellow oil. LC/MS 270.0 (M+1).

Step H: Methyl3-(1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperidin-4-yl)-1-naphthoate,trifluoroacetic acid salt. To a solution of 30 mg (0.093 mmol) ofintermediate 5 in 2 mL of anhydrous dichloromethane at −78° C. was added0.016 mL (0.20 mmol) of 1-methylimidazole followed by 0.008 mL (0.1mmol) of methanesulfonyl chloride. The resulting mixture was stirredwith gradual warming to ambient temperature over 20 min, then re-cooledto 0° C. A solution of 25 mg (0.093 mmol) of methyl3-piperidin-4-yl-1-naphthoate in 1 mL of anhydrous dichloromethane wasadded and the reaction mixture was allowed to warm to ambienttemperature over 16 h. The reaction mixture was quenched with asaturated aqueous ammonium chloride solution (5 mL) and the layers wereseparated. The aqueous layer was extracted with dichloromethane (2×5 mL)and the combined organic layers were washed with brine (5 mL), driedover magnesium sulfate, filtered and concentrated in vacuo. The cruderesidue was purified by reverse phase HPLC (TMC Pro-Pac C18; 10-90%0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid inwater gradient). The pure fractions were concentrated in vacuo to yieldthe title compound as a white solid. LC/MS 592.2 (M+1).

Step I:3-(1-{[1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}piperidin-4-yl)-1-naphthoicacid, trifluoroacetic acid salt. To a solution of 55 mg (0.093 mmol) ofthe product from step H in 2 mL of anhydrous tetrahydrofuran was added60 mg (0.47 mmol) of potassium trimethylsilanolate and the resultingmixture was stirred at ambient temperature for 16 h. The reaction wasthen concentrated in vacuo and purified by reverse phase HPLC (TMCPro-Pac C18; 10-90% 0.01% trifluoroacetic acid in acetonitrile/0.01%trifluoroacetic acid in water gradient). The pure fractions werelyophilized overnight to give the title compound as a white solid. ¹HNMR (CD₃OD): δ 8.83-8.85 (m, 1H), 8.16 (s, 1H), 7.88-7.93 (m, 2H),7.31-7.55 (m, 5H), 6.87-7.15 (m, 5H) 4.81-4.90 (m, 2H), 3.93-3.97 (m,2H), 3.05-3.46 (m, 3H), 2.38 (s, 3H), 1.91-2.09 (m, 3H), 1.30-1.43 (m,3H). LC-MS 578.3 (M+1):

EXAMPLE 573-(1-{[1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-hydroxypiperidin-4-yl)-1-naphthoicAcid, Trifluoroacetic Acid Salt

Step A: Methyl 3-(4-hydroxypiperidin-4-yl)-1-naphthoate, trifluoroaceticacid salt. To a solution of 113 mg (0.300 mmol) of tert-Butyl4-hydroxy-4-[4-(methoxycarbonyl)-2-naphthyl]piperidine-1-carboxylate(Example 28, Step E) in 2 mL of dichloromethane was added 0.125 mL (1.64mmol) of trifluoroacetic acid and the resulting mixture stirred atambient temperature for 30 min. The reaction mixture was thenconcentrated in vacuo to yield the crude title compound as a colorlessoil.

Step B: Methyl3-(1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-hydroxypiperidin-4-yl)-1-naphthoate.To a solution of 29 mg (0.084 mmol) of Intermediate 5 in 2 mL ofanhydrous dichloromethane at 0° C. was added 0.015 mL (0.18 mmol) of1-methylimidazole followed by 0.007 mL (0.09 mmol) of methanesulfonylchloride. The resulting mixture was stirred with gradual warming toambient temperature over 20 min, then re-cooled to 0° C. A solution of24 mg (0.084 mmol) of methyl 3-(4-hydroxypiperidin-4-yl)-1-naphthoate,trifluoroacetic acid salt in 1 mL of anhydrous dichloromethane was thenadded and the reaction mixture was allowed to warm to ambienttemperature over 16 h. The reaction mixture was then quenched with asaturated aqueous ammonium chloride solution (5 mL) and the layers wereseparated. The aqueous layer was extracted with dichloromethane (2×5 mL)and the combined organic layers were washed with brine (5 mL), driedover magnesium sulfate, filtered and concentrated in vacuo. The cruderesidue was purified by reverse phase HPLC (TMC Pro-Pac C18; 10-90%0.01% trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid inwater gradient). The pure fractions were concentrated in vacuo to yieldthe title compound as a colorless oil.

Step C:3-(1-{[1-(3-Ethoxyphenyl-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4hydroxypiperidin-4-yl)-1-naphthoicacid, trifluoroacetic acid salt. To a solution of 51 mg (0.084 mmol) ofmethyl3-(1-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-hydroxypiperidin-4-yl)-1-naphthoatein 2 mL of anhydrous tetrahydrofuran was added 54 mg (0.42 mmol) ofpotassium trimethylsilanolate and the resulting mixture was stirred atambient temperature for 16 h. The reaction was then concentrated invacuo and purified by reverse phase HPLC (TMC Pro-Pac C18; 10-90% 0.01%trifluoroacetic acid in acetonitrile/0.01% trifluoroacetic acid in watergradient). The pure fractions were lyophilized overnight to give thetitle compound as a white solid. ¹H NMR (CD₃OD): δ 8.87-8.89 (m, 1H),8.44-8.75 (s, 1H), 8.13-8.22 (m, 1H), 7.95-7.99 (m, 2H), 7.32-7.60 (m,4H), 6.88-7.14 (m, 5H), 4.67 (m, 2H), 3.81-3.99 (m, 3H), 3.45-3.49 (m,1H) 3.00 (s, 1H), 2.87 (s, 1H), 2.26-2.40 (m, 4H), 1.95-2.02 (m, 2H),1.32-1.35 (m, 3H), LC/MS 594.0 (M+1).

Biological Assays A. Cholecystokinin-1 Receptor (CCK1R) andCholecystokinin-2 Receptor (CCK2R) Binding Assays

Cells were cultured to confluence and harvested by aspirating culturemedium and rinsed twice with 1×PBS without Mg⁺⁺ and Ca⁺⁺. 3 mL of CellDissociate Solution was added to each T-175 flask until all cellsdissociated and then an additional 15 ml 1×PBS without Mg⁺⁺ and Ca⁺⁺ wasadded to each flask. Dissociated cells were collected in a centrifugetube by centrifuging at 1000 rpm for 10 min. The cell pellet washomogenized at 4° C. using a Polytron (setting 40, 20 stokes) in about10 mL/T175 flask membrane preparation buffer (10 mM Tris pH 7.4, 0.01 mMPefabloc, 10 μM phosphoramidon and 40 μg/mL Bacitracin). Aftercentrifugation at 2200 rpm (1000×g) for 10 min at 4° C., the supernatantwas transferred to a clean centrifuge tube and spun at 18,000 rpm(38,742×g) for 15 min. at 4° C. Membranes were resuspended with theabove membrane preparation buffer (1000 μl per T-175 flask),homogenized, aliquoted, quickly frozen in liquid nitrogen and stored at−80° C. The specific binding of ¹²⁵I-Bolton Hunter-CCK-8S to CCK1R orCCK2R was measured by filtration binding assay in 96 well plate format.0.5 μg membrane/well in binding buffer (50 mM Tris pH 7.4, 5 mM MgCl₂,200 μg/mL Bacitracin and protease inhibitor cocktail) was mixed withagonists in 1% DMSO (final concentration) and 0.1 nM ¹²⁵I-BoltonHunter-CCK-8S was added. After incubation for 1-2 hrs at roomtemperature, membrane-bound ¹²⁵I-Bolton Hunter-CCK8S was separated fromthe free ¹²⁵I-Bolton Hunter-CCK8S by filtering through GF/C filterspresoaked in 0.2% BSA solution. The filters were washed with ice-coldwashing buffer (50 mM Tris pH 7.4, 10 mM MgCl₂, 2 mM EDTA and 0.04%Tween 20). The radioactivity was determined by adding 30 μl ofmicroscintillant/well after each plate was dried at room temperatureovernight or placed at 55° C. for 30 mins. A Packard Top Count was thenused to read each filter plate. The data in cpms was plotted vs. the logmolar concentration of receptor ligand (compound). The IC₅₀ was reportedas the inflection point of the resulting sigmoidal curve. The maximuminhibition observed at the highest compound concentration was reportedfor compounds which do not generate a curve.

B. Cell Culture of Cholecystokinin-1 Receptor (CCK1R) andCholecestokinin-2 Receptor (CCK2R) Cell Lines Stable CHO cell linesexpressing the human CCK1R and CCK2R cDNA and stable HEK293 cell linesexpressing the human CCK2R cDNA were generated using standard cellbiology techniques. One CCK1R clone identified as CHO_WT23 was used forboth FLIPR and IP3 functional and binding assays. One CCK2R clone calledCHO_B101 was used for FLIPR functional assays and another CCK2R clone,CHO_hCCK2R, was used for IP3 functional assays. Both WT23 and B101 cellswere routinely cultured in T175 flasks in Iscoves Modified Dulbecco'sMedium (Invitrogen #12440-046) supplemented with 10% FBS (cat#SH30070.03, Hyclone, Logan, Utah), 1×HT Supplement (0.1 mM SodiumHypoxanthine and 16 μM Thymidine), 100 units/mL Penicillin-G and 100μg/mL Streptomycin, 2 mM L-Glutamine and 1 mg/mL Geneticin.hCCK2R/CHO/Flip-in cells were routinely cultured in T175 flasks in F-12Nutrient Mixture (Ham) supplemented with 10% FBS (cat #SH30070.03,Hyclone, Logan, Utah), 100 units/mL Penicillin-G and 100 μg/mLStreptomycin, 2 mM L-Glutamine and 150 μg/mL Hygromycin. One Hek293hCCK2R clone identified as Hek293_hCCK2R#37 was used for binding assays.Hek293_hCCK2R#37 cells were routinely cultured in T175 flasks inDulbecco's Modified Eagle Medium, with high glucose (Invitrogen Cat#11965-084) supplemented with 10% FBS (cat #SH30070.03, Hyclone, Logan,Utah), 25 mM of HEPES Buffer Solution (Invitrogen cat #15630-080), 500μg/mL Geneticin (Invitrogen cat #10131-027) and 200 μg/mL Hygromycin.Cells were grown as attached monolayers in tissue culture flasks underappropriate media in an incubator at 37° C. with 5% CO₂—Cells werepassed 1:5 for CHO_WT23, B101 and CHO_hCCK2R cells and 1:3 for HEK293_hCCK2R#37 twice a week. Cell culture media, antibiotics, FetalBovine Serum were all from Invitogen Technologies Inc. unless otherwisespecified.

C. Cholecystokinin-1 Receptor (CCK1R) and Cholecystokinin-2 Receptor(CCKR) Functional Assays

1) FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices,Sunnyvale, Calif.) CHO_WT23 and B101 cells cultured as described abovewere detached with Trypsin-EDTA and 20 μl volume of cells were seeded in384 well plate at 62,500 cells/mL The cells grew overnight at 37° C.with 5% CO₂ in a humidified atmosphere. On the day of the assay, thecells were loaded with 20 μl/well of No-wash assay buffer (HBSS, 0.1%BSA, 20 mM HEPES, 2.5 mM Probenecid and 1.6 mM TR40 Quenching Solution)containing 8 μM Fluo-4 AM in the dark at room temperature for 1.5 hrs.Agonists were dissolved in DMSO and diluted into assay buffer. 13.3μl/well of 4× concentration of agonist solution was added to cells whilemeasuring fluorescence. The EC₅₀ for activation of the CCK1R or CCK2Rreceptor was reported as the inflection point of the resulting sigmoidalcurve.

2) Inositol Phosphate SPA Assay (IP3) to Measure IP3 Accumulation

This functional assay was performed in a 96-well format. On the firstday, 75 μl of CHO cells at 62,500/mL were plated on poly-D-lysineplates. On the afternoon of the next day, the plates were aspirated, andthe cells were washed with PBS w/o Mg⁺⁺, Ca⁺⁺. Next 150 μl of³H-inositol labeling media, Inositol-free DMEM media ICN #1642954supplemented with 10% FBS, 1× pen/strep/glutamine to which³H-myo-inositol (NEN #NET114A) was added, 1 mCi/mL, 25 Ci/mmol diluted1:150 in loading medium (final specific radioactivity of 1 μCi/150 μl).After 18 hours of labeling, 5 μl 300 mM LiCl was added to the wells,mixed, and incubated for 20 minutes at 37° C., then 1.5 μl DMSO of 200×compounds were added to wells and incubated for an additional 90 minutesat 37° C. Plates were aspirated, and then the reaction was terminatedand cells were lysed with the addition of 60 μl 10 mM formic acid for 60minutes at room temperature. 20 μl of lysate was transferred toclear-bottom Opti-plates which contained RNA binding YSi SPA-beads(Amersham RPNQ0013) that were suspended in 10% glycerol at 1 mg beads/70μl of solution and dispensed at 70 μl per well. After mixing, the platessit at room temperature for 2 hrs and were then counted using a WallacMicrobeta reader. The EC₅₀ for activation of the CCK1F or CCK2R receptorwas calculated from the titration curve of the compounds.

D. In-Vivo Overnight Food Intake and Body Weight in C57 Lean Male Mice

Methods: Male C57 mice, approximately 8 weeks old (weighingapproximately 25 g) were individually housed and acclimated for severaldays prior to testing. Mice were orally dosed (PO; n=8) with eithervehicle controls (10% Tween-water) or CCK1R agonists (various doses). Aknown CB1 inverse agonist, AM251 (3 mg/kg) was used as the positivecontrol for inter- and intra-experimental control. CCK1R agonists weredosed (PO) approximately 60-120 minutes prior to the onset of the darkcycle. Overnight food intake (g) and body weight (g) (±SEM) werecollected and analyzed. All data were presented as mean±SEM (n=8).Statistical significance was calculated using Student's t-test todetermine whether compared the groups were statistically distinct.Differences were considered significant when p<0.05.

Compounds useful in the present invention decrease overnight food intakeby at least 10% and/or decrease body weight overnight by at least 1%relative to placebo.

E. Mouse Gallbladder Emptying Assay for CCK-1R Binding Specificity

Methods: Male CD-1 mice, approximately 7-8 weeks old (weighing 25 g)were housed (8 mice per cage), and fasted for 18 hours with ad libaccess to water. Mice were orally dosed (PO; n=8) with either vehiclecontrols (10% Tween-water) or CCK1R agonists (various doses) for 4 h.After 4 h, mice were deeply anesthetized with CO₂ inhalant; bloodsamples were drawn via cardiac puncture and stored at −20° C. (forfuture assays). Gall bladders were isolated, removed and weighed.Gallbladder weights were normalized to body weight (g/kg) and comparedto vehicle control group. The entire assay typically requiredapproximately 30-40 minutes for tissue collection. All data werepresented as mean±SEM (n=8) and Statistical significance was calculatedusing Student's t-test to determine whether compared the groups werestatistically distinct. Differences were considered significant whenp<0.05.

Representative compounds of the present invention were tested and foundto bind to the cholecystokinin-1 receptor. Representative compounds ofthe present invention were found to have IC₅₀ values less than or equalto 500 nM. Representative compounds of the present invention were alsotested in the functional assay and found to activate thecholecystokinin-1 receptor with EC₅₀ values less than or equal to 500nM.

Examples of Pharmaceutical Compositions

As a specific embodiment of an oral composition of a composition of thepresent invention, 5 mg of Example 1 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size O hard gelatin capsule.

As another specific embodiment of an oral composition of a compound ofthe present invention, 2.5 mg of Example 1 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size 0 hard gelatin capsule.

While the invention has been described and illustrated in reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferred dosesas set forth hereinabove may be applicable as a consequence ofvariations in the responsiveness of the subject or mammal being treatedobesity, diabetes and obesity-related disorders, or for otherindications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and embodiments of the present invention. Itis intended, therefore, that the invention be limited only by the scopeof the claims which follow and that such claims be interpreted asbroadly as is reasonable.

1-23. (canceled)
 24. A method of treating diabetes mellitus, obesity oran obesity related disorder, which method comprises administering to amammalian patient in need of such treatment a therapeutically effectiveamount of a compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein X is N or CR¹⁶;R¹, R², R³ and R⁴ are each selected from the group consisting of: (1)hydrogen, (2) halogen, (3) —OH, (4) —C₁₋₆alkyl, and (5) —C₁₋₆alkoxy,wherein alkyl and alkoxy are unsubstituted or substituted with one tofive substituents selected from halogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy,and R² and R³ or R³ and R⁴ together with the atoms to which they areattached form a 4-8 membered ring containing 0-2 heteroatomsindependently selected from oxygen, and wherein the 4-8 membered ring isunsubstituted or substituted with a substituent selected from OH,halogen, C₁₋₆alkyl, and C₁₋₆alkoxy; R⁵, R⁶ and R⁷ are each independentlyselected from the group consisting of: (1) hydrogen, (2) halogen, (3)—C₁₋₆alkyl, and (4) —C₁₋₆alkoxy, wherein alkyl and alkoxy areunsubstituted or substituted with one to five substituents selected fromhalogen, OH, C₁₋₆alkyl, and C₁₋₆alkoxy; R⁸ is hydrogen; R⁹ is hydrogen;each R¹⁹ is independently selected from the group consisting of: (1) Cl,(2) —CH═CHCO₂H, (3) —C(O)morpholine, (4) —C(O)pyrrolidine, (5)—C(O)piperidine, (6) —CO₂H, (7) —CO₂CH₂-phenyl, (8) —CO₂CH₃, (9)—(CH₂)₂CO₂H, (10) —CO₂tetrahydropyran, (11) —CONH₂, (12) —CONHCH₃, (13)—CONHCH₂CH₃, (14) —CON(CH₂CH₃)₂, (15) —CON(CH₃)₂, (16) —CONHCH(CH₃)₂,(17) —CONHcyclopropyl, (18) —CONHphenyl, (19) —C(O)NHcyclopentyl, (20)—C(O)NH(CH₂)₁₋₆OH, (21) —C(O)NHtetrahydropyran, (22) —CONHCH₂CO₂H, (23)—CON(CH₃)CH₂CO₂H, (24) —CONHCOC(CH₃)₃, (25) —C(O)NHCH(CO₂CH₂phenyl)₂,(26) —C(O)NHCH(CO₂CH₂CH₃)₂, and (27) tetrazole, wherein the alkyl,alkene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituentsand —(CH₂)_(n) are unsubstituted or substituted with one to eightsubstituents selected from —C₁₋₆alkyl, oxo, halogen, —C₁₋₆alkoxy,—(CH₂)_(n)OH, —(CH₂)_(n)CN, —(CH₂)_(n)CF₃, —(CH₂)_(n)SO₃H,—(CH₂)_(n)CO₂H, —(CH₂)_(n)CO₂C₁₋₆alkyl, and —(CH₂)_(n)CO₂C₂₋₆alkene, andalkyl and alkoxy are unsubstituted or substituted with one to fivesubstituents independently selected from halogen, —OH, —SO₃H, —CO₂H, and—CO₂C₁₋₆alkyl; R¹⁶ is selected from the group consisting of: hydrogen,—OH, —C₁₋₆alkyl unsubstituted or substituted with —OH or phenyl, and—C₁₋₆alkoxy; each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; and mis 1 and p is 0, and a therapeutically effective amount of a secondagent selected from the group consisting of an insulin-sensitizer, acholesterol lowering agent, and an anti-obesity agent.
 25. The method ofclaim 24, wherein the second agent is an insulin-sensitizer.
 26. Themethod of claim 25, wherein the insulin-sensitizer is selected from thegroup consisting of a PPARγ antagonist, a dipeptidyl peptidase 4inhibitor, a glucagon like peptide 1 agonist, and a biguanidine.
 27. Themethod of claim 26, wherein the dipeptidyl peptidase 4 inhibitor issitagliptin.
 28. The method of claim 26, wherein the biguandine isselected from the group consisting of metformin and phenformin.
 29. Themethod of claim 24, wherein the second agent is a cholesterol loweringagent.
 30. The method of claim 29, wherein the cholesterol loweringagent is selected from the group consisting of a HMG-CoA reductaseinhibitor, a PPARα agonist, and a cholesterol absorption inhibitor. 31.The method of claim 30, wherein the HMG-CoA reductase inhibitor isselected from the group consisting of atorvastatin, itavastatin,fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, andsimvastatin.
 32. The method of claim 30, wherein the cholesterolabsorption inhibitor is ezetimibe.
 33. The method of claim 30, whereinthe PPAα agonist is selected from the group consisting of beclofibrate,benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, andgemfibrozil.
 34. The method of claim 24, wherein the second agent is ananti-obesity agent.
 35. The method of claim 34, wherein the anti-obesityagent is selected from the group consisting of a neuropeptide Y1antagonist, a neuropeptide Y2 agonist, a neuropeptide Y5 antagonist, apancreatic lipase inhibitor, a cannabinoid CB1 receptor antagonist orinverse agonist, a melanin-concentrating hormone receptor antagonist, amelanocortin 4 receptor agonist, a ghrelin receptor antagonists, aneurokinin-1 receptor antagonists, a peptide YY analog, a serotonergicagent, a 5HT2c agonist, and a bombesin receptor subtype 3 agonist. 36.The method of claim 35, wherein the serotonergic agent is selected fromthe group consisting of fenfluramine, dexfenfluramine, phentermine, andsibutramine.